(hetero)arylamide compound for inhibiting protein kinase activity

ABSTRACT

Provided are a (hetero)arylamide compound as shown in formula (I) having an inhibitory effect on protein kinase activity, a pharmaceutically acceptable salt, a stereoisomer, a solvate or hydrate thereof, a pharmaceutical composition including the compound or a derivative thereof, and a method for preparing the compound. The compound can be used as an irreversible inhibitor for protein kinase, for preparing a plurality of drugs including an anti-tumour drug.

FIELD OF THE PRESENT DISCLOSURE

The present disclosure belongs to the pharmaceutical field. Inparticular, the present disclosure relates to (hetero)arylamidecompounds which inhibit the tyrosine kinase activity of Abelson protein(Abl1), Abelson-related protein (Abl2) and related chimeric proteins,particularly Bcr-Abl1, relates to pharmaceutical compositions containingthe same, and methods for their preparation and use thereof.

BACKGROUND OF THE PRESENT DISCLOSURE

Protein tyrosine kinases (PTKs) are a class of kinases that are involvedin proteinases, which catalyze the transfer of γ-phosphate on ATP toprotein tyrosine residues, and catalyze the phosphorylation of thephenolic hydroxyl groups on various protein tyrosine residues, therebyin turn activate functional proteins. Protein tyrosine kinases play animportant role in the cellular signal transduction pathway, regulating aseries of physiological and biochemical processes such as cell growth,differentiation and death. Abnormal expression of protein tyrosinekinase can lead to disturbances in cell proliferation regulation, whichin turn leads to tumorigenesis. In addition, the abnormal expression ofprotein tyrosine kinase is also closely related to tumor invasion andmetastasis, tumor angiogenesis, and chemotherapy resistance of tumors.

The tyrosine kinase expressed by the Bcr-Abl fusion gene can causechanges in cell proliferation, adhesion and survival properties, leadingto the occurrence of various tumors. Inhibition of Bcr-Abl tyrosinekinase can effectively inhibit tumor growth.

ABL-001 (also known as Asciminib, chemical name(R)—N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(1H-pyrazol-5-yl)nicotinamide,which has the following structural formula) is an allosteric inhibitorof ABL1 kinase developed by Novartis Pharmaceuticals Co., Ltd., whichinactivates ABL1 by targeting its myristoyl pocket, and is effective inpreventing the emergence of drug resistance in the application of ATPinhibitors and/or allosteric inhibitors when used in combination withinhibitors of BCR-ABL tyrosine kinase that compete with ATP. ABL-001 hasbeen shown to be effective in eradicating CML in a mouse model whencombined with the second-generation BCR-ABL inhibitor nilotinib (AndrewA. Wylie et al. (2017) Nature 543, 733-737). Novartis is developing aclinical treatment regimen of ABL-001 in combination with variousATP-competitive BCR-ABL inhibitors, including imatinib, nilotinib, anddasatinib.

Therefore, it is necessary to further develop novel Bcr-Abl inhibitors.

SUMMARY OF THE PRESENT DISCLOSURE

The present disclosure provides a novel (hetero)arylamide compound and acomposition comprising the same and use thereof, which have betterBcr-Abl kinase inhibitory activity (especially for T315I mutation),lower side effects and/or better pharmacodynamics/pharmacokineticproperties, and thus can be used to treat diseases mediated by Bcr-Ablkinase.

In this regard, the technical solution adopted by the present disclosureis as follows:

In the first aspect, the present disclosure provides a (hetero)arylamidecompound represented by formula (I), or a pharmaceutically acceptablesalt, a stereoisomer, a solvate or a hydrate thereof:

wherein:

Y₁ is selected from CR_(a) or N;

Y is independently selected from CR₈ or N;

R₁ is selected from hydrogen, halo, nitrile, nitro, C₁₋₆ alkyl or C₁₋₆haloalkyl, wherein the said C₁₋₆ alkyl or C₁₋₆ haloalkyl is optionallysubstituted by R_(1a) group;

R₂ is selected from hydrogen, C₁₋₆ alkyl or C₁₋₆ haloalkyl, wherein thesaid C₁₋₆ alkyl or C₁₋₆ haloalkyl is optionally substituted by R_(2a)group;

Z is a chemical bond, O, S(O)₀₋₂ or NR;

or —Z—R₂ together form —SF₅;

Ar is

wherein X₁ is selected from O, S or NR_(b), X₂ to X₈ are independentlyselected from CR or N;

and when X₁ is O or S, one of X₂, X₃ and X₄ is C atom that connects theparent core; when X₁ is NR_(b), one of X₂, X₃ and X₄ is C atom thatconnects the parent core and wherein at least one of them is N;

Het is

wherein X₉ is selected from O, S, NR_(b) or C(R)₂;

m is 0, 1 or 2;

In is 0, 1, 2, 3, 4, 5 or 6;

R_(a) is independently selected from hydrogen, halo, nitrile, nitro,hydroxy, —NH₂, —NHC₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂, C₁₋₆ alkyl, C₁₋₆haloalkyl or C₁₋₆ alkoxyl;

R_(b) is independently selected from hydrogen, C₁₋₆ alkyl or C₁₋₆haloalkyl;

R_(1a), R_(2a) and R are independently selected from hydrogen, halo,hydroxy, —NH₂, —NHC₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkoxyl, C₃₋₇ cycloalkyl, C₃₋₇ heterocyclyl, C₆₋₁₀ arylor C₅₋₁₀ heteroaryl;

or two R groups on the same or adjacent atoms may together form C₃₋₇cycloalkyl, C₃₋₇ heterocyclyl, C₆₋₁₀ aryl or C₅₋₁₀ heteroaryl.

In another aspect, the disclosure provides a pharmaceutical compositioncomprising a compound disclosed herein and a pharmaceutically acceptableexcipient. In a particular embodiment, the compound disclosed herein isprovided in the pharmaceutical composition in an effective amount. In aparticular embodiment, the compound disclosed herein is provided in atherapeutically effective amount. In a particular embodiment, thecompound disclosed herein is provided in a prophylactically effectiveamount.

In another aspect, the disclosure provides a pharmaceutical compositioncomprising a compound disclosed herein and a pharmaceutically acceptableexcipient.

In another aspect, the disclosure provides a kit containing a compounddisclosed herein and other therapeutic agents, and pharmaceuticallyacceptable carriers, adjuvants or vehicles.

In another aspect, the disclosure provides the use of a compounddisclosed herein in the manufacture of a medicament for the treatmentand/or prevention of diseases caused by Bcr-Abl.

In another aspect, the disclosure provides a method of treating and/orpreventing diseases caused by Bcr-Abl in a subject, comprisingadministering to the subject a compound disclosed herein or acomposition disclosed herein.

In another aspect, the disclosure provides a compound disclosed hereinor a composition disclosed herein, for use in the treatment and/orprevention of diseases caused by Bcr-Abl.

In a specific embodiment, the disease may be selected from the groupconsisting of: solid tumor, sarcoma, acute lymphocytic leukemia, acutemyeloid leukemia, chronic lymphocytic leukemia, chronic myeloidleukemia, gastrointestinal stromal tumor, thyroid cancer, gastriccancer, rectal cancer, multiple myeloma, neoplasia, and otherproliferative disease or proliferative diseases.

In a specific embodiment, the Bcr-Abl caused disease is chronic myeloidleukemia, gastrointestinal stromal tumor, acute myeloid leukemia,thyroid cancer, metastatic invasive cancer, or a combination thereof.

In another aspect, the compounds disclosed herein also have thepotential to treat or prevent diseases or disorders associated withabnormally activated kinase activity of wild-type Abl, includingnon-malignant diseases or disorders, such as CNS diseases in particularneurodegenerative diseases (for example Alzheimer's, Parkinson'sdiseases), motoneuroneuron diseases (amyotophic lateral sclerosis),muscular dystrophies, autoimmune and inflammatory diseases (diabetes andpulmonary fibrosis), viral infections, and prion diseases.

In a specific embodiment, the compound is administered orally,subcutaneously, intravenously or intramuscularly. In a specificembodiment, the compound is administered chronically.

Other objects and advantages of the present disclosure will be apparentto those skilled in the art from the following specific embodiments,examples and claims.

Definitions Chemical Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅ and C₅₋₆ alkyl.

It should be understood that when described herein any of the moietiesdefined forth below may be substituted with a variety of substituents,and that the respective definitions are intended to include suchsubstituted moieties within their scope as set out below. Unlessotherwise stated, the term “substituted” is to be defined as set outbelow.

“C₁₋₆ alkyl” refers to a radical of a straight-chain or branchedsaturated hydrocarbon group having from 1 to 6 carbon atoms, and it isalso referred to herein as “lower alkyl”. In some embodiments, C₁₋₄alkyl is particularly preferred. Examples of alkyl groups include methyl(C₁), ethyl (C₂), n-propyl (C₃), isopropyl (C₃), n-butyl (C₄) tert-butyl(C₄), sec-butyl (C₄), iso-butyl (C₄), n-pentyl (C₅), 3-pentanyl (C₅),amyl (C₅), neopentyl (C₅), 3-methyl-2-butanyl (C₅), tertiary amyl (C₅),and n-hexyl (C₆). Unless otherwise specified, each instance of an alkylgroup is independently optionally substituted, i.e., unsubstituted (an“unsubstituted alkyl”) or substituted (a “substituted alkyl”) with oneor more substituents; e.g. for instance from 1 to 5 substituents, 1 to 3substituents, or 1 substituent. In certain embodiments, the alkyl groupis unsubstituted C₁₋₆ alkyl (e.g. —CH₃). In certain embodiments, thealkyl group is substituted C₁₋₆ alkyl.

“C₁₋₆ alkoxy” refers to the group —OR wherein R is a substituted orunsubstituted C₁₋₆ alkyl group. In some embodiments, C₁₋₄ alkoxy groupis particularly preferred. Specific alkoxy groups include, but are notlimited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,tert-butoxy, sec-butoxy, n-pentyloxy, n-hexyloxy and 1,2-dimethylbutoxy.

“Halo” or “halogen” means fluorine (F), chlorine (Cl), bromine (Br) andiodine (I). In some embodiments, the halo group is F, —Cl or Br. In someembodiments, the halogen group is Cl. In some embodiments, the halogengroup is F. In some embodiments, the halogen group is Br.

Thus, “C₁₋₆ haloalkyl” refers to the above “C₁₋₆ alkyl”, which issubstituted by one or more halo groups. In some embodiments, C₁₋₄haloalkyl group is particularly preferred, and more preferably C₁₋₂haloalkyl group. Exemplary haloalkyl groups include, but are not limitedto, —CF₃, —CH₂F, —CHF₂, —CClF₂, —CHFCH₂F, —CH₂CHF₂, —CF₂CF₃, —CF₂CClF₂,—CF₂CH₃, —CCl₃, —CH₂Cl, —CHCl₂, 2,2,2-trifluoro-1,1-dimethyl-ethyl, andthe like.

“C₃₋₇ cycloalkyl” refers to a radical of a non-aromatic cyclichydrocarbon group having from 3 to 7 ring carbon atoms and zeroheteroatoms. In some embodiments, C₃₋₆ cycloalkyl is especiallypreferred, and C₅₋₆ cycloalkyl is more preferred. Cycloalkyl alsoincludes ring systems wherein the cycloalkyl ring, as defined above, isfused with one or more aryl or heteroaryl groups wherein the point ofattachment is on the cycloalkyl ring, and in such instances, the numberof carbons continue to designate the number of carbons in the cycloalkylring system. Exemplary cycloalkyl groups include, but is not limited to,cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄) cyclobutenyl (C₄)cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl(C₆), cyclohexadienyl (C₆), cycloheptyl (C₇), cycloheptenyl (C₇),cycloheptadienyl (C₇), cycloheptatrienyl (C₇) and the like. Unlessotherwise specified, each instance of a cycloalkyl group isindependently optionally substituted, i.e., unsubstituted (an“unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”)with one or more substituents. In certain embodiments, the cycloalkylgroup is unsubstituted C₃₋₇ cycloalkyl. In certain embodiments, thecycloalkyl group is a substituted C₃₋₇ cycloalkyl.

“C₃₋₇ heterocyclyl” refers to a radical of a 3- to 7-memberednon-aromatic ring system having ring carbon atoms and 1 to 4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon. Inheterocyclyl groups that contain one or more nitrogen atoms, the pointof attachment can be a carbon or nitrogen atom, as valency permits. Insome embodiments, C₃₋₆ heterocyclyl is especially preferred, which is aradical of a 3- to 6-membered non-aromatic ring system having ringcarbon atoms and 1 to 3 ring heteroatoms. In some embodiments, C₅₋₆heterocyclyl is more preferred, which is a radical of a 5- to 6-memberednon-aromatic ring system having ring carbon atoms and 1 to 3 ringheteroatoms. Unless otherwise specified, each instance of heterocyclylis independently optionally substituted, i.e., unsubstituted (an“unsubstituted heterocyclyl”) or substituted (a “substitutedheterocyclyl”) with one or more substituents. In certain embodiments,the heterocyclyl group is unsubstituted C₃₋₇ heterocyclyl. In certainembodiments, the heterocyclyl group is substituted C₃₋₇ heterocyclyl.Heterocyclyl also includes ring systems wherein the heterocyclyl ring,as defined above, is fused with one or more cycloalkyl groups, whereinthe point of attachment is on the cycloalkyl ring; or wherein theheterocyclyl ring, as defined above, is fused with one or more aryl orheteroaryl groups, wherein the point of attachment is on theheterocyclyl ring; and in such instances, the number of ring memberscontinue to designate the number of ring members in the heterocyclylring system. Exemplary 3-membered heterocyclyl groups containing oneheteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl.Exemplary 4-membered heterocyclyl groups containing one heteroatominclude, without limitation, azetidinyl, oxetanyl and thietanyl.Exemplary 5-membered heterocyclyl groups containing one heteroatominclude, without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyland pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, dioxolanyl,oxasulfuranyl disulfuranyl, and oxazolidin-2-one. Exemplary 5-memberedheterocyclyl groups containing three heteroatoms include, withoutlimitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary6-membered heterocyclyl groups containing one heteroatom include,without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl,and thianyl. Exemplary 6-membered heterocyclyl groups containing twoheteroatoms include, without limitation, piperazinyl, morpholinyl,dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containingthree heteroatoms include, without limitation, triazinanyl. Exemplary7-membered heterocyclyl groups containing one heteroatom include,without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary5-membered heterocyclyl groups fused to a C₆ aryl ring (also referred toherein as a 5,6-bicyclic heterocyclic ring) include, without limitation,indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groupsfused to an aryl ring (also referred to herein as a 6,6-bicyclicheterocyclic ring) include, without limitation, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and the like.

“C₆₋₁₀ aryl” refers to a radical of a monocyclic or polycyclic (e.g.,bicyclic) 4n+2 aromatic ring system (e.g., having 6, 10 π electronsshared in a cyclic array) having 6-10 ring carbon atoms and zeroheteroatoms. In some embodiments, an aryl group has six ring carbonatoms (“C₆ aryl”; e.g., phenyl). In some embodiments, an aryl group hasten ring carbon atoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and2-naphthyl). Aryl also includes ring systems wherein the aryl ring, asdefined above, is fused with one or more cycloalkyl, or heterocyclylgroups wherein the radical or point of attachment is on the aryl ring,and in such instances, the number of carbon atoms continue to designatethe number of carbon atoms in the aryl ring system. Unless otherwisespecified, each instance of an aryl group is independently optionallysubstituted, i.e., unsubstituted (an “unsubstituted aryl”) orsubstituted (a “substituted aryl”) with one or more substituents. Incertain embodiments, the aryl group is unsubstituted C₆₋₁₀ aryl. Incertain embodiments, the aryl group is substituted C₆₋₁₀ aryl.

“C₅₋₁₀ heteroaryl” refers to a radical of a 5-10 membered monocyclic orbicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 n electronsshared in a cyclic array) having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen and sulfur. In heteroaryl groups that contain one ormore nitrogen atoms, the point of attachment can be a carbon or nitrogenatom, as valency permits. Heteroaryl bicyclic ring systems can includeone or more heteroatoms in one or both rings. Heteroaryl furtherincludes ring systems wherein the heteroaryl ring, as defined above, isfused with one or more cycloalkyl, or heterocyclyl groups wherein thepoint of attachment is on the heteroaryl ring, and in such instances,the number of ring members continue to designate the number of ringmembers in the heteroaryl ring system. In some embodiments, C₅₋₆heteroaryl is especially preferred, which is a radical of a 5-6 memberedmonocyclic or bicyclic 4n+2 aromatic ring system having ring carbonatoms and 1-4 ring heteroatoms. Unless otherwise specified, eachinstance of a heteroaryl group is independently optionally substituted,i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a“substituted heteroaryl”) with one or more substituents. In certainembodiments, the heteroaryl group is unsubstituted 5- to 10-memberedheteroaryl. In certain embodiments, the heteroaryl group is substituted5- to 10-membered heteroaryl. Exemplary 5-membered heteroaryl groupscontaining one heteroatom include, without limitation, pyrrolyl, furanyland thiophenyl. Exemplary 5-membered heteroaryl groups containing twoheteroatoms include, without limitation, imidazolyl, pyrazolyl,oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-memberedheteroaryl groups containing three heteroatoms include, withoutlimitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary5-membered heteroaryl groups containing four heteroatoms include,without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groupscontaining one heteroatom include, without limitation, pyridinyl.Exemplary 6-membered heteroaryl groups containing two heteroatomsinclude, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.Exemplary 6-membered heteroaryl groups containing three or fourheteroatoms include, without limitation, triazinyl and tetrazinyl,respectively. Exemplary 7-membered heteroaryl groups containing oneheteroatom include, without limitation, azepinyl, oxepinyl, andthiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, withoutlimitation, indolyl, isoindolyl, indazolyl, benzotriazolyl,benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl,benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, andpurinyl. Exemplary 6,6-bicyclic heteroaryl groups include, withoutlimitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl,cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

“Nitrile group” represents the group —CN.

“Nitro group” represents the group —NO₂.

Other Definitions

The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, Berge et al.,describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptablesalts of the compounds of the present disclosure include those derivedfrom suitable inorganic and organic acids and bases.

A “subject” to which administration is contemplated includes, but is notlimited to, humans (i.e., a male or female of any age group, e.g., apediatric subject (e.g. infant, child, adolescent) or adult subject(e.g., young adult, middle-aged adult or senior adult)) and/or anon-human animal, e.g., a mammal such as primates (e.g., cynomolgusmonkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents,cats, and/or dogs. In certain embodiments, the subject is a human. Incertain embodiments, the subject is a non-human animal. The terms“human,” “patient,” and “subject” are used interchangeably herein.

Disease, disorder, and condition are used interchangeably herein.

As used herein, and unless otherwise specified, the terms “treat,”“treating” and “treatment” contemplate an action that occurs while asubject is suffering from the specified disease, disorder or condition,which reduces the severity of the disease, disorder or condition, orretards or slows the progression of the disease, disorder or condition(“therapeutic treatment”), and also contemplates an action that occursbefore a subject begins to suffer from the specified disease, disorderor condition (“prophylactic treatment”).

In general, the “effective amount” of a compound refers to an amountsufficient to elicit the desired biological response. As will beappreciated by those of ordinary skill in this art, the effective amountof a compound disclosed herein may vary depending on such factors as thedesired biological endpoint, the pharmacokinetics of the compound, thedisease being treated, the mode of administration, and the age, health,and condition of the subject. An effective amount encompassestherapeutically effective amount and prophylactically effective amount.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of a compound is an amount sufficient to provide atherapeutic benefit in the treatment of a disease, disorder orcondition, or to delay or minimize one or more symptoms associated withthe disease, disorder or condition. A therapeutically effective amountof a compound means an amount of therapeutic agent, alone or incombination with other therapies, which provides a therapeutic benefitin the treatment of the disease, disorder or condition. The term“therapeutically effective amount” can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of disease orcondition, or enhances the therapeutic efficacy of another therapeuticagent.

As used herein, and unless otherwise specified, a “prophylacticallyeffective amount” of a compound is an amount sufficient to prevent adisease, disorder or condition, or one or more symptoms associated withthe disease, disorder or condition, or prevent its recurrence. Aprophylactically effective amount of a compound means an amount of atherapeutic agent, alone or in combination with other agents, whichprovides a prophylactic benefit in the prevention of the disease,disorder or condition. The term “prophylactically effective amount” canencompass an amount that improves overall prophylaxis or enhances theprophylactic efficacy of another prophylactic agent.

“Bcr-Abl” refers to a fusion protein created from the N-terminal exonsof the breakpoint cluster region (BCR) gene and the major C-terminalpart (exons 2-11) of the Abelson (ABL1) gene. The most common fusiontranscripts encode for a 210-kDa protein (p210 Bcr-Abl1), while rarertanscripts encode a 190-kDa protein (p190 Bcr-Abl1) and a 230-kDaprotein (p230 Bcr-Abl). The Abi sequences of these proteins contains anAbl1 tyrosine kinase domain which is tightly regulated in the wild-typeprotein, but constitutively activated in the Bcr-Abl1 fusion proteins.This deregulated tyrosine kinase interacts with multiple cellularsignalling pathways leading to transformation and deregulatedproliferation of the cells.

1 “Bcr-Abl1 mutants” refers to the numerous single site mutations inBcr-Abl1 including: Glu255→Lys, Glu255→Val, Thr315→Ile, Met244→Val.Phe317→Leu, Leu248→Val, Met343→Thr, Gly250→Ala, Met351→Thr, Gly250→Glu,Glu355→Gly, Gln252→His, Phe358→Ala, Gln252→Arg, Phe359→Val, Tyr253→His,Val379→Ile, Tyr253→Phe, Phe382→Leu, Glu255→Lys, Leu387→Met, Glu255→Val,His396→Pro, Phe311→Ile, His396→Arg, Phe311→Leu, Ser417→Tyr, Thr315→Ile.Glu459→Lys and Phe486→Ser.

“C-Abl” refers to the full length gene product of anon-mutated wild-typeAbl1.

DETAILED DESCRIPTION OF THE EMBODIMENTS Compound

In the present disclosure, “compound disclosed herein” refers to thefollowing compound of formula (I), (la) and (Ib), or a pharmaceuticallyacceptable salt, a stereoisomer, a solvate, or a hydrate thereof.

In one embodiment, the present disclosure relates to a compound offormula (I), or a pharmaceutically acceptable salt, a stereoisomer, asolvate or a hydrate thereof:

wherein:

Y₁ is selected from CR_(a) or N; Y is independently selected from CR_(a)or N;

R₁ is selected from hydrogen, halo, nitrile, nitro, C₁₋₆ alkyl or C₁₋₆haloalkyl, wherein the said C₁₋₆ alkyl or C₁₋₆ haloalkyl is optionallysubstituted by R_(1a) group;

R₂ is selected from hydrogen. C₁₋₆ alkyl or C₁₋₆ haloalkyl, wherein thesaid C₁₋₆ alkyl or C₁₋₆ haloalkyl is optionally substituted by R₂ group;

Z is a chemical bond, O, S(O)₀₋₂ or NR_(b);

or —Z—R₂ together form —SF₅;

Ar is

wherein X₁ is selected from O, S or NR_(b), X₂ to X₈ are independentlyselected from CR or N;

and when X₁ is O or S, one of X₂, X₃ and X₄ is C atom that connects theparent core; when X₁ is NR_(b), one of X₂, X₃ and X₄ is C atom thatconnects the parent core and wherein at least one of them is N;

Het is

wherein X₉ is selected from O, S, NR_(b) or C(R)₂;

m is 0, 1 or 2;

In is 0, 1, 2, 3, 4, 5 or 6;

R_(a) is independently selected from hydrogen, halo, nitrile, nitro,hydroxy, —NH₂, —NHC₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂, C₁₋₆ alkyl, C₁₋₆haloalkyl or C₁₋₆ alkoxyl;

R_(b) is independently selected from hydrogen, C₁₋₆ alkyl or C₁₋₆haloalkyl;

R_(1a), R_(2a) and R are independently selected from hydrogen, halo,hydroxy, —NH₂, —NHC₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkoxyl, C₃₋₇ cycloalkyl, C₃₋₇ heterocyclyl, C₆₋₁₀ arylor C₅₋₁₀ heteroaryl;

or two R groups on the same or adjacent atoms may together form C₃₋₇cycloalkyl, C₃₋₇ heterocyclyl, C₆₋₁₀ aryl or C₅₋₁₀ heteroaryl.

In another embodiment, the present disclosure relates to the abovecompound, wherein

Ar is

wherein X₁ is S, X₂ to X₄ are independently selected from CR or N; andone of X₂, X₃ and X₄ is C atom that connects the parent core;

or, Ar is selected from the following groups that are optionallysubstituted by one or two R:

In another embodiment, the present disclosure relates to the abovecompound, which is formula (Ia), or a pharmaceutically acceptable salt,a stereoisomer, a solvate or a hydrate thereof:

wherein, Ar and Het are as defined herein.

In another embodiment, the present disclosure relates to the abovecompound, or a pharmaceutically acceptable salt, a stereoisomer, asolvate or a hydrate thereof, wherein:

Ar is

wherein, X₁ to X₄ are as defined herein;

or, Ar is selected from the following groups that are optionallysubstituted by one or two R:

wherein, R and R_(b) are as defined herein.

In another embodiment, the present disclosure relates to the abovecompound, or a pharmaceutically acceptable salt, a stereoisomer, asolvate or a hydrate thereof, wherein:

Ar is

wherein, X₅ to X₈ are as defined herein;

or, Ar is selected from the following groups that are optionallysubstituted by R:

wherein, R is as defined herein.

In another embodiment, the present disclosure relates to the abovecompound, or a pharmaceutically acceptable salt, a stereoisomer, asolvate or a hydrate thereof, wherein:

Het is

wherein, X₉ is C(R)₂, and m, n and R are as defined herein:

or, Het is selected from the following groups that are optionallysubstituted by one, two, three or more R:

wherein R is as defined herein;

or, Het is selected from the following groups:

In another embodiment, the present disclosure relates to the abovecompound, or a pharmaceutically acceptable salt, a stereoisomer, asolvate or a hydrate thereof, wherein:

Het is

wherein, one X₉ is selected from O, S or NR_(b), and the optionallypresent other X₉ is C(R)₂, and m, n, R and R_(b) are as defined herein;

or, Het is selected from the following groups:

In another embodiment, the present disclosure relates to the abovecompound, which is formula (Ib), or a pharmaceutically acceptable salt,a stereoisomer, a solvate or a hydrate thereof:

wherein:

Ar is

wherein X₂ to X₄ are independently selected from CR or N, and one of X₂,X₃ and X₄ is C atom that connects the parent core;

or, Ar is selected from the following groups that are optionallysubstituted by one or two R:

R is selected from hydrogen, halo, hydroxy, —NH₂, —NHC₁₋₆ alkyl, —N(C₁₋₆alkyl)₂.

In another embodiment, the present disclosure relates to the abovecompound, which is formula (Ib), or a pharmaceutically acceptable salt,a stereoisomer, a solvate or a hydrate thereof:

wherein:

Ar is selected from the following groups that are optionally substitutedby one or two R:

R is selected from hydrogen, halo, hydroxy, —NH₂, —NHC₁₋₆ alkyl, —N(C₁₋₆alkyl)₂.

In another embodiment, the present disclosure relates to the abovecompound, which is formula (Ib), or a pharmaceutically acceptable salt,a stereoisomer, a solvate or a hydrate thereof:

wherein:

Ar is selected from the following groups that are optionally substitutedby one or two R:

R is selected from hydrogen, hydroxyl.

In another embodiment, the present disclosure relates to the abovecompound, which is formula (Ib), or a pharmaceutically acceptable salt,a stereoisomer, a solvate or a hydrate thereof:

wherein:

Ar is selected from the following groups that are optionally substitutedby one or two R:

R is selected from hydrogen, halo, hydroxyl.

In another embodiment, the present disclosure relates to the abovecompound, which is formula (Ib), or a pharmaceutically acceptable salt,a stereoisomer, a solvate or a hydrate thereof:

wherein:

Ar is selected from the following groups that are optionally substitutedby one or two R:

R is selected from hydrogen, hydroxyl.

In another embodiment, the present disclosure relates to the abovecompound, which is formula (Ib), or a pharmaceutically acceptable salt,a stereoisomer, a solvate or a hydrate thereof:

wherein:

Ar is selected from the following groups that are optionally substitutedby one or two R:

R is selected from hydrogen, halo, hydroxyl.

In another embodiment, the present disclosure relates to the abovecompound, which is formula (Ib), or a pharmaceutically acceptable salt,a stereoisomer, a solvate or a hydrate thereof, wherein:

wherein:

Ar is

wherein X₂ to X₄ are independently selected from CR or N, and one of X₂,X₃ and X₄ is C atom that connects the parent core and wherein at leastone of them is N;

or, Ar is selected from the following groups that are optionallysubstituted by one R:

R_(b) is selected from hydrogen, C₁₋₆ alkyl or C₁₋₆ haloalkyl;

R is selected from hydrogen, halo, hydroxy, —NH₂, —NHC₁₋₆ alkyl, —N(C₁₋₆alkyl)₂.

In another embodiment, the present disclosure relates to the abovecompound, which is formula (Ic), or a pharmaceutically acceptable salt,a stereoisomer, a solvate or a hydrate thereof, wherein:

wherein:

Ar is selected from the following groups that are optionally substitutedby one or two R:

R is selected from hydrogen, halo, hydroxy, —NH₂, —NHC₁₋₆ alkyl, —N(C₁₋₆alkyl)₂.

In another embodiment, the present disclosure relates to the abovecompound, which is formula (Ic), or a pharmaceutically acceptable salt,a stereoisomer, a solvate or a hydrate thereof, wherein:

wherein:

Ar is selected from the following groups

In another embodiment, the present disclosure relates to the abovecompound, which is formula (Ic), or a pharmaceutically acceptable salt,a stereoisomer, a solvate or a hydrate thereof, wherein:

wherein:

Ar is selected from the following groups:

Y₁ and Y

In one specific embodiment, Y₁ is N; in another specific embodiment, Y₁is CR_(a); in another specific embodiment, Y₁ is CH.

In one specific embodiment, Y is CR_(a); in another specific embodiment,Y is N; in another specific embodiment, Y is CH.

R₁

In one specific embodiment, R₁ is selected from hydrogen, halo, nitrile,nitro, C₁₋₆ alkyl or C₁₋₆ haloalkyl; in another specific embodiment, R₁is selected from hydrogen, halo, nitrile, nitro or C₁₋₆ alkyl; inanother specific embodiment. R₁ is selected from hydrogen or halo; inanother specific embodiment, R₁ is hydrogen; in another specificembodiment, R₁ is halo (F, Cl, Br or I); in another specific embodiment,R₁ is nitrile; in another specific embodiment, R₁ is nitro; in anotherspecific embodiment, R₁ is C₁₋₆ alkyl (methyl, ethyl, propyl, isopropyl,butyl, iso-butyl, tert-butyl, pentyl, iso-pentyl, hexyl, and the like);in another specific embodiment. R is C₁₋₆ haloalkyl (—CF₃, —CH₂F, —CHF₂,—CClF₂—CHFCH₂F, —CH₂CHF₂, —CF₂CF₃, —CF₂CClF₂, —CF₂CH₃, —CCl₃, —CH₂Cl,—CHCl₂, 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like).

R₂ and Z

In one specific embodiment, R₂ is selected from hydrogen, C₁₋₆ alkyl orC₁₋₆ haloalkyl; in another specific embodiment. R₂ is selected from C₁₋₆alkyl or C₁₋₆ haloalkyl; in another specific embodiment, R₂ is hydrogen;in another specific embodiment, R₂ is C₁₋₆ alkyl (methyl, ethyl, propyl,isopropyl, butyl, iso-butyl, tert-butyl, pentyl, iso-pentyl, hexyl, andthe like); in another specific embodiment, R₂ is C₁₋₆ haloalkyl (—CF₃,—CH₂F, —CHF₂, —CClF₂, —CHFCH₂F, —CH₂CHF₂, —CF₂CF₃, —CF₂CClF₂, —CF₂CH₃,—CCl₃, —CH₂Cl, —CHCl₂, 2,2,2-trifluoro-1,1-dimethyl-ethyl, and thelike).

In one specific embodiment, Z is a chemical bond; in another specificembodiment, Z is O; in another specific embodiment, Z is S(O)₀₋₂; inanother specific embodiment, Z is NR_(b); in another specificembodiment, Z is NH.

In one specific embodiment, —Z—R₂ together form —SF₅.

Ar and X₁ to X₈

In one specific embodiment. Ar is

wherein X is O or S; in more specific embodiment, Ar is

in more specific embodiment, Ar is

In the above specific embodiment regarding Ar, X₂ is CR; in anotherspecific embodiment, X₂ is CH; in another specific embodiment, X₂ is N.In the above embodiment regarding Ar, X₃ is CR; in another specificembodiment, X₃ is CH; in another specific embodiment, X₃ is N. In theabove specific embodiment regarding Ar, X₄ is CR; in another specificembodiment, X₄ is CH; in another specific embodiment, X₄ is N.

In the above mentioned embodiment, one of X₂, X₃ and X₄ is C atom thatconnects the parent core; in one specific embodiment, X₂ is C atom thatconnects the parent core; in another specific embodiment, X₃ is C atomthat connects the parent core; in another specific embodiment, X₄ is Catom that connects the parent core.

In more specific embodiment, Ar is

In the above specific embodiment regarding Ar, X₂ is CR; in anotherspecific embodiment, X₂ is CH; in another specific embodiment, X₂ is N.In the above embodiment regarding Ar, X₃ is CR in another specificembodiment, X₃ is CH; in another specific embodiment. X₃ is N. In theabove specific embodiment regarding Ar, X₄ is CR; in another specificembodiment, X₄ is CH; in another specific embodiment, X₄ is N.

In the above mentioned embodiment, one of X₂, X₃ and X₄ is C atom thatconnects the parent core and wherein at least one of them is N; in onespecific embodiment, X₂ is C atom that connects the parent core, X₃ isN; in another specific embodiment, X₂ is C atom that connects the parentcore, X₄ is N; in another specific embodiment, X₃ is C atom thatconnects the parent core, X₂ is N; in another specific embodiment, X₃ isC atom that connects the parent core, X₄ is N; in another specificembodiment, X₄ is C atom that connects the parent core, X₂ is N; inanother specific embodiment, X₄ is C atom that connects the parent core.X₃ is N.

In another specific embodiment, Ar is

In the above specific embodiment regarding Ar, X₅ is CR; in anotherspecific embodiment, X₅ is CH; in another specific embodiment, X₅ is N.In the above specific embodiment regarding Ar, X₆ is CR; in anotherspecific embodiment, X₆ is CH; in another specific embodiment, X₆ is N.In the above specific embodiment regarding Ar, X₇ is CR; in anotherspecific embodiment, X₇ is CH; in another specific embodiment, X₇ is N.In the above specific embodiment regarding Ar, X₈ is CR; in anotherspecific embodiment, X₈ is CH; in another specific embodiment, X₈ is N.

In more specific embodiment, Ar is the following groups that areoptionally substituted by one or two R:

in more specific embodiment, Ar is the following groups that areoptionally substituted by one R:

in more specific embodiment, Ar is the following groups that areoptionally substituted by R:

Het, X₉, m and n

In one specific embodiment, Het is

In the above specific embodiment regarding Het, X₁ is O; in anotherspecific embodiment, X₉ is S; in another specific embodiment, X₉ isNR_(b); in another specific embodiment, X₉ is C(R)₂. In the abovespecific embodiment regarding Het, m is 0; in another specificembodiment, m is 1; in another specific embodiment, m is 2. In the abovespecific embodiment regarding Het, n is 0; in another specificembodiment, n is 1; in another specific embodiment, n is 2; in anotherspecific embodiment, n is 3; in another specific embodiment, n is 4; inanother specific embodiment, n is 5; in another specific embodiment, nis 6.

In more specific embodiment, Het is

wherein, X₉ is C(R)₂. In more specific embodiment, Het the followinggroups that are optionally substituted by one, two, three or more R:

in more specific embodiment, Het is selected from the following groups:

in more specific embodiment, Het is

wherein, one X₉ is selected from O, S or NR_(b), and the optionallypresent other X₉ is C(R)₂; in more specific embodiment, Het is selectedfrom the following groups:

R_(a), R_(b), R_(1a), R_(2a) and R

In one specific embodiment, R_(a) is independently selected fromhydrogen, halo, nitrile, nitro, hydroxy, —NH₂, —NHC₁₋₆ alkyl, —N(C₁₋₆alkyl)₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl or C₁₋₆ alkoxyl; in another specificembodiment. R_(a) is hydrogen; in another specific embodiment, R_(a) ishalo; in another specific embodiment, R_(a) is nitrile; in anotherspecific embodiment, R_(a) is nitro; in another specific embodiment,R_(a) is hydroxy; in another specific embodiment, R_(a) is —NH₂; inanother specific embodiment, R_(a) is —NHC₁₋₆ alkyl; in another specificembodiment, R_(a) is —N(C₁₋₆ alkyl)₂; in another specific embodiment,R_(a) is C₁₋₆ alkyl; in another specific embodiment, R_(a) is C₁₋₆haloalkyl; in another specific embodiment, R_(a) is C₁₋₆ alkoxyl.

In one specific embodiment, R is independently selected from hydrogen,C₁₋₆ alkyl or C₁₋₆ haloalkyl; in another specific embodiment. R_(b) ishydrogen; in another specific embodiment, R is C₁₋₆ alkyl; in anotherspecific embodiment, R_(b) is C₁₋₆ haloalkyl.

In one specific embodiment, R_(1a), R_(2a) and R are independentlyselected from hydrogen, halo, hydroxy, —NH₂, —NHC₁₋₆ alkyl, —N(C₁₋₆alkyl)₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxyl, C₃₋₇ cycloalkyl, C₃₋₇heterocyclyl, C₆₋₁₀ aryl or C₅₋₁₀ heteroaryl; in another specificembodiment, R_(1a), R_(2a) and R are hydrogen; in another specificembodiment, R_(1a), R_(2a) and R are halo; in another specificembodiment, R_(1a), R_(2a) and R are hydroxy; in another specificembodiment, R_(1a), R_(2a) and R are —NH₂; in another specificembodiment. R_(1a), R_(2a) and R are —NHC₁₋₆ alkyl; in another specificembodiment, R_(1a), R_(2a) and R are —N(C₁₋₆ alkyl)₂; in anotherspecific embodiment, R_(1a), R_(2a) and R are C₁₋₆ alkyl; in anotherspecific embodiment, R_(1a), R_(2a) and R are C₁₋₆ haloalkyl; in anotherspecific embodiment, R_(1a), R_(2a) and R are C₁₋₆ alkoxyl; in anotherspecific embodiment, R_(1a), R_(2a) and R are C₃₋₇ cycloalkyl; inanother specific embodiment. R_(1a), R_(2a) and R are C₃₋₇ heterocyclyl;in another specific embodiment, R_(1a), R_(2a) and R are C₆₋₁₀ aryl; inanother specific embodiment, R_(1a), R_(2a) and R are C₅₋₁₀ heteroaryl.

In one specific embodiment, two R groups on the same or adjacent atomsmay together form C₃₋₇ cycloalkyl, C₃₋₇ heterocyclyl, C₆₋₁₀ aryl orC₅₋₁₀ heteroaryl; in another specific embodiment, two R groups on thesame or adjacent atoms may together form C₃₋₇ cycloalkyl; in anotherspecific embodiment, two R groups on the same or adjacent atoms maytogether form C₃₋₇ heterocyclyl. In another specific embodiment, two Rgroups on the same or adjacent atoms may together form C₆₋₁₀ aryl; inanother specific embodiment, two R groups on the same or adjacent atomsmay together form C₅₋₁₀ heteroaryl.

Any technical solution in any one of the above specific embodiments, orany combination thereof, may be combined with any technical solution inother specific embodiments or any combination thereof. For example, anytechnical solution of Y₁ or any combination thereof may be combined withany technical solution of Y, R₁, R₂, Z, Ar, X₁ to X₉, Het, m, n, R_(a),R_(b), R_(1a), R_(2a) and R or any combination thereof. The presentdisclosure is intended to include all combination of such technicalsolutions, which are not exhaustively listed here to save space.

In specific embodiments, the compounds disclosed herein are selectedfrom the following compounds:

Compounds described herein can comprise one or more asymmetric centers,and thus can exist in various stereoisomeric forms, e.g., enantiomersand/or diastereomers. For example, the compounds described herein can bein the form of an individual enantiomer, diastereomer or geometricisomer (such as cis- and trans-isomer), or can be in the form of amixture of stereoisomers, including racemic mixtures and mixturesenriched in one or more stereoisomer. Isomers can be isolated frommixtures by methods known to those skilled in the art, including chiralhigh pressure liquid chromatography (HPLC) and the formation andcrystallization of chiral salts; or preferred isomers can be prepared byasymmetric syntheses.

Those skilled in the art will appreciate that many organic compounds canform complexes with solvents that react in or precipitate or crystallizefrom the solvent. These complexes are referred to as “solvates.” Whenthe solvent is water, the complex is referred to as a “hydrate.” Thedisclosure encompasses all solvates of the compounds disclosed herein.

Pharmacology and Efficacy

The compounds disclosed herein show therapeutic efficacy especially ondiseases or disorders that are dependent on the activity of Bcr-Abl1. Inparticular, the compounds disclosed herein inhibit the ATP binding siteof Bcr-Abl1 (including wild-type Bcr-Abl1 and/or its mutations(including T315I mutations)).

Carcinoma cells utilize invapodia to degrade the extra cellular matrixduring tumor invasion and metastasis. Abl kinase activity is requiredfor Src-induced invapodia formation, regulating distinct stages ofinvapodia assembly and function. The compounds disclosed herein,therefore, as inhibitors of Abl, have the potential to be used astherapies for the treatment of metastatic invasive carcinomas.

An inhibitor of c-Abl kinase can be used to treat brain cancers:including Glioblastoma which is the most common and most aggressivemalignant primary brain tumor in which the expression of c-Abl isimmunohistochemically detectable in a subset of patients. Therefore anew c-Abl inhibitor with high brain exposure represents a solidtherapeutic approach for glioblastoma and other brain cancers.

Compounds disclosed herein can be useful in the treatment of viruses.For example, viral infections can be mediated by Abl1 kinase activity,as in the case of pox viruses and the Ebola virus. Imatinib andnilotinib have been shown to stop the release of Ebola viral particlesfrom infected cells, in vitro. Compounds disclosed herein that inhibitc-Abl kinase, therefore, can be expected to reduce the pathogen'sability to replicate.

Parkinson's disease is the second most prevalent chronicneurodegenerative disease with the most common familialautosomal-recessive form being caused by mutations in the E3 ubiquitinligase, parkin. Recent studies showed that activated c-ABL was found inthe striatum of patients with sporadic Parkinson's disease.Concomitantly, parkin was tyrosine-phosphorylated, causing loss of itsubiquitin ligase and cytoprotective activities as indicated by theaccumulation of parkin substrates.

The compounds or compositions disclosed herein are also useful in thetreatment of diseases, disorders or conditions mediated by Bcr-Ablkinase: respiratory diseases, allergies, rheumatoid arthritis,osteoarthritis, rheumatic disorders, psoriasis, ulcerative colitis,Crohn's disease, septic shock, proliferative disorders, atherosclerosis,allograft rejection after transplantation, diabetes, stroke, obesity orrestenosis, leukemia, stromal tumor, thyroid cancer, systemicmastocytosis, eosinophilia syndrome, fibrosis, polyarthritis,scleroderma, lupus erythematosus, graft versus host disease,neurofibromatosis, pulmonary hypertension, Alzheimer's disease,seminoma, dysgerminoma, mast cell tumor, lung cancer, bronchialcarcinoma, dysgerminoma, testicular intraepithelial neoplasia, melanoma,breast cancer, neuroblastoma, papillary/follicular parathyroidhyperplasia/adenoma, colon cancer, colorectal adenoma, ovarian cancer,prostate cancer, glioblastoma, brain tumor malignant glioma, pancreaticcancer, malignant pleura tumor, hemangioblastoma, hemangioma, kidneycancer, liver cancer, adrenal cancer, bladder cancer, stomach cancer,rectal cancer, vaginal cancer, cervical cancer, endometrial cancer,multiple myeloma, neck and head tumors, neoplasia and otherproliferative disease or proliferative diseases, or the combinationthereof.

Pharmaceutical Compositions, Formulations and Kits

In another aspect, the disclosure provides a pharmaceutical compositioncomprising a compound of the present disclosure (also referred to as the“active ingredient”) and a pharmaceutically acceptable excipient. Incertain embodiments, the pharmaceutical composition comprises aneffective amount of the compound of the present disclosure. In certainembodiments, the pharmaceutical composition comprises a therapeuticallyeffective amount of the compound of the present disclosure. In certainembodiments, the pharmaceutical composition comprises a prophylacticallyeffective amount of the compound of the present disclosure.

A pharmaceutically acceptable excipient for use in the presentdisclosure refers to a non-toxic carrier, adjuvant or vehicle which doesnot destroy the pharmacological activity of the compound formulatedtogether. Pharmaceutically acceptable carriers, adjuvants, or vehiclesthat can be used in the compositions of the present disclosure include,but are not limited to, ion exchangers, alumina, aluminum stearate,lecithin, serum proteins (e.g., human serum albumin), buffer substances(such as phosphate), glycine, sorbic acid, potassium sorbate, a mixtureof partial glycerides of saturated plant fatty acids, water, salt orelectrolyte (such as protamine sulfate), disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salt, silica gel,magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based materials,polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax,polyethylene-polyoxypropylene block polymers, polyethylene glycol andlanolin.

The present disclosure also includes kits (e.g., pharmaceutical packs).Kits provided may include a compound disclosed herein, other therapeuticagents, and a first and a second containers (eg, vials, ampoules,bottles, syringes, and/or dispersible packages or other suitablecontainer) containing the compound disclosed herein or other therapeuticagents. In some embodiments, kits provided can also optionally include athird container containing a pharmaceutically acceptable excipient fordiluting or suspending the compound disclosed herein and/or othertherapeutic agent. In some embodiments, the compound disclosed hereinprovided in the first container and the other therapeutic agentsprovided in the second container is combined to form a unit dosage form.

The following formulation examples illustrate representativepharmaceutical compositions that may be prepared in accordance with thisdisclosure. The present disclosure, however, is not limited to thefollowing pharmaceutical compositions.

Exemplary Formulation 1—Tablets: A compound of the present disclosuremay be admixed as a dry powder with a dry gelatin binder in anapproximate 1:2 weight ratio. A minor amount of magnesium stearate isadded as a lubricant. The mixture is formed into 0.3-30 mg tablets(0.1-10 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 2—Tablets: A compound of the present disclosuremay be admixed as a dry powder with a dry gelatin binder in anapproximate 1:2 weight ratio. A minor amount of magnesium stearate isadded as a lubricant. The mixture is formed into 30-90 mg tablets (10-30mg of active compound per tablet) in a tablet press.

Exemplary Formulation 3—Tablets: A compound of the present disclosuremay be admixed as a dry powder with a dry gelatin binder in anapproximate 1:2 weight ratio. A minor amount of magnesium stearate isadded as a lubricant. The mixture is formed into 90-150 mg tablets(30-50 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 4—Tablets: A compound of the present disclosuremay be admixed as a dry powder with a dry gelatin binder in anapproximate 1:2 weight ratio. A minor amount f magnesium stearate isadded as a lubricant. The mixture is formed into 150-240 mg tablets(50-80 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 5—Tablets: A compound of the present disclosuremay be admixed as a dry powder with a dry gelatin binder in anapproximate 1:2 weight ratio. A minor amount of magnesium stearate isadded as a lubricant. The mixture is formed into 240-270 mg tablets(80-90 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 6—Tablets: A compound of the present disclosuremay be admixed as a dry powder with a dry gelatin binder in anapproximate 1:2 weight ratio. A minor amount of magnesium stearate isadded as a lubricant. The mixture is formed into 270-450 mg tablets(90-150 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 7—Tablets: A compound of the present disclosuremay be admixed as a dry powder with a dry gelatin binder in anapproximate 1:2 weight ratio. A minor amount of magnesium stearate isadded as a lubricant. The mixture is formed into 450-900 mg tablets(150-300 mg of active compound) in a tablet press.

Exemplary Formulation 8—Capsules: A compound of the present disclosuremay be admixed as a dry powder with a starch diluent in an approximate1:1 weight ratio. The mixture is filled into 250 mg capsules (25 mg ofactive compound per capsule).

Exemplary Formulation 9—Liquid: A compound of the present disclosure(125 mg) may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) andthe resultant mixture may be blended, passed through a No. 10 mesh U.S.sieve, and then mixed with a previously made solution ofmicrocrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50mg) in water. Sodium benzoate (10 mg), flavor, and color are dilutedwith water and added with stirring. Sufficient water may then be addedto produce a total volume of 5 mL.

Exemplary Formulation 10—Injection: A compound of the present disclosuremay be dissolved or suspended in a buffered sterile saline injectableaqueous medium to a concentration of approximately 5 mg/mL.

Administration

The pharmaceutical composition provided by the present disclosure can beadministered by a variety of routes including, but not limited to, oraladministration, parenteral administration, inhalation administration,topical administration, rectal administration, nasal administration,oral administration, vaginal administration, administration by implantor other means of administration. For example, parenteral administrationas used herein includes subcutaneous administration, intradermaladministration, intravenous administration, intramuscularadministration, intra-articular administration, intraarterialadministration, intrasynovial administration, intrasternaladministration, intracerebroventricular administration, intralesionaladministration, and intracranial injection or infusion techniques.

Generally, the compounds provided herein are administered in aneffective amount. The amount of the compound actually administered willtypically be determined by a physician, in the light of the relevantcircumstances, including the condition to be treated, the chosen routeof administration, the actual compound administered, the age, weight,and response of the individual patient, the severity of the patient'ssymptoms, and the like.

When used to prevent the disorder disclosed herein, the compoundsprovided herein will be administered to a subject at risk for developingthe condition, typically on the advice and under the supervision of aphysician, at the dosage levels described above. Subjects at risk fordeveloping a particular condition generally include those that have afamily history of the condition, or those who have been identified bygenetic testing or screening to be particularly susceptible todeveloping the condition.

The pharmaceutical compositions provided herein can also be administeredchronically (“chronic administration”). Chronic administration refers toadministration of a compound or pharmaceutical composition thereof overan extended period of time, e.g., for example, over 3 months, 6 months,1 year, 2 years, 3 years, 5 years, etc, or may be continuedindefinitely, for example, for the rest of the subject's life. Incertain embodiments, the chronic administration is intended to provide aconstant level of the compound in the blood, e.g., within thetherapeutic window over the extended period of time.

The pharmaceutical compostions of the present disclosure may be furtherdelivered using a variety of dosing methods. For example, in certainembodiments, the pharmaceutical composition may be given as a bolus,e.g., in order to raise the concentration of the compound in the bloodto an effective level. The placement of the bolus dose depends on thesystemic levels of the active ingredient desired through the body, e.g.,an intramuscular or subcutaneous bolus dose allows a slow release of theactive ingredient, while a bolus delivered directly to the veins (e.g.,through an IV drip) allows a much faster delivery which quickly raisesthe concentration of the active ingredient in the blood to an effectivelevel. In other embodiments, the pharmaceutical composition may beadministered as a continuous infusion. e.g., by IV drip, to providemaintenance of a steady-state concentration of the active ingredient inthe subject's body. Furthermore, in still yet other embodiments, thepharmaceutical composition may be administered as first as a bolus dose,followed by continuous infusion.

The compositions for oral administration can take the form of bulkliquid solutions or suspensions, or bulk powders. More commonly,however, the compositions are presented in unit dosage forms tofacilitate accurate dosing. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient. Typical unitdosage forms include prefilled, premeasured ampules or syringes of theliquid compositions or pills, tablets, capsules or the like in the caseof solid compositions. In such compositions, the compound is usually aminor component (from about 0.1 to about 50% by weight or preferablyfrom about 1 to about 40% by weight) with the remainder being variousvehicles or excipients and processing aids helpful for forming thedesired dosing form.

With oral dosing, one to five and especially two to four and typicallythree oral doses per day are representative regimens. Using these dosingpatterns, each dose provides from about 0.01 to about 20 mg/kg of thecompound provided herein, with preferred doses each providing from about0.1 to about 10 mg/kg, and especially about 1 to about 5 mg/kg.

Transdermal doses are generally selected to provide similar or lowerblood levels than are achieved using injection doses, generally in anamount ranging from about 0.01 to about 20% by weight, preferably fromabout 0.1 to about 20% by weight, preferably from about 0.1 to about 10%by weight, and more preferably from about 0.5 to about 15% by weight.

Injection dose levels range from about 0.1 mg/kg/hour to at least 10mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to% hours. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kg ormore may also be administered to achieve adequate steady state levels.The maximum total dose is not expected to exceed about 2 g/day for a 40to 80 kg human patient.

Liquid forms suitable for oral administration may include a suitableaqueous or nonaqueous vehicle with buffers, suspending and dispensingagents, colorants, flavors and the like. Solid forms may include, forexample, any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatin; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring.

Injectable compositions are typically based upon injectable sterilesaline or phosphate-buffered saline or other injectable excipients knownin the art. As before, the active compound in such compositions istypically a minor component, often being from about 0.05 to 10% byweight with the remainder being the injectable excipient and the like.

Transdermal compositions are typically formulated as a topical ointmentor cream containing the active ingredient(s). When formulated as aointment, the active ingredients will typically be combined with eithera paraffinic or a water-miscible ointment base. Alternatively, theactive ingredients may be formulated in a cream with, for example anoil-in-water cream base. Such transdermal formulations are well-known inthe art and generally include additional ingredients to enhance thedermal penetration of stability of the active ingredients orFormulation. All such known transdermal formulations and ingredients areincluded within the scope provided herein.

The compounds provided herein can also be administered by a transdermaldevice. Accordingly, transdermal administration can be accomplishedusing a patch either of the reservoir or porous membrane type, or of asolid matrix variety.

The above-described components for orally administrable, injectable ortopically administrable compositions are merely representative. Othermaterials as well as processing techniques and the like are set forth inPart 8 of Remington s Pharmaceutical Sciences, 17th edition, 1985, MackPublishing Company, Easton, Pa., which is incorporated herein byreference.

The compounds of the present disclosure can also be administered insustained release forms or from sustained release drug delivery systems.A description of representative sustained release materials can be foundin Remington's Pharmaceutical Sciences.

The present disclosure also relates to the pharmaceutically acceptableformulations of a compound of the present disclosure. In one embodiment,the formulation comprises water. In another embodiment, the formulationcomprises a cyclodextrin derivative. The most common cyclodextrins areα-, β- and γ-cyclodextrins consisting of 6, 7 and 8 α-1,4-linked glucoseunits, respectively, optionally comprising one or more substituents onthe linked sugar moieties, which include, but are not limited to,methylated, hydroxyalkylated, acylated, and sulfoalkyether substitution.In certain embodiments, the cyclodextrin is a sulfoalkyl etherβ-cyclodextrin, e.g, for example, sulfobutyl ether β-cyclodextrin, alsoknown as Captisol. See, e.g., U.S. Pat. No. 5,376,645. In certainembodiments, the formulation comprises hexapropyl-β-cyclodextrin (e.g.,10-50% in water).

Treatment

The compounds disclosed herein are also useful in the treatment ofdiseases, disorders or conditions mediated by Bcr-Abl kinase:respiratory diseases, allergies, rheumatoid arthritis, osteoarthritis,rheumatic disorders, psoriasis, ulcerative colitis, Crohn's disease,septic shock, proliferative disorders, atherosclerosis, allograftrejection after transplantation, diabetes, stroke, obesity orrestenosis, leukemia, stromal tumor, thyroid cancer, systemicmastocytosis, eosinophilia syndrome, fibrosis, polyarthritis,scleroderma, lupus erythematosus, graft versus host disease,neurofibromatosis, pulmonary hypertension, Alzheimer's disease,seminoma, dysgerminoma, mast cell tumor, lung cancer, bronchialcarcinoma, dysgerminoma, testicular intraepithelial neoplasia, melanoma,breast cancer, neuroblastoma, papillary/follicular parathyroidhyperplasia/adenoma, colon cancer, colorectal adenoma, ovarian cancer,prostate cancer, glioblastoma, brain tumor, malignant glioma, pancreaticcancer, malignant pleura tumor, hemangioblastoma, hemangioma, kidneycancer, liver cancer, adrenal cancer, bladder cancer, stomach cancer,rectal cancer, vaginal cancer, cervical cancer, endometrial cancer,multiple myeloma, neck and head tumors, neoplasia and otherproliferative disease or proliferative diseases, or the combinationthereof.

The present disclosure thus provides the use of the compound disclosedherein, especially in the treatment of diseases and disorders mediatedby inappropriate Bcr-Abl activity.

The inappropriate Bcr-Abl activity referred to herein is any Bcr-Ablactivity that deviates from the normal Bcr-Abl activity expected in aparticular mammalian subject. Inappropriate Bcr-Abl activity may takethe form of, for instance, an abnormal increase in activity, or anaberration in the timing and or control of Bcr-Abl activity. Suchinappropriate activity may result then, for example, from overexpressionor mutation of the protein kinase leading to inappropriate oruncontrolled activation.

In a further embodiment, the present disclosure is directed to methodsof regulating, modulating, or inhibiting Bcr-Abl for the preventionand/or treatment of disorders related to unregulated or inappropriateBcr-Abl activity.

In another embodiment, the said disorder mediated by Bcr-Abl activity isrespiratory diseases. In another embodiment, the said disorder isproliferative diseases. In yet another embodiment, the said disorder iscancer. In another embodiment, the said disorder is leukemia.

In another embodiment, compounds disclosed herein can also be useful inthe treatment of neural degeneration. While native c-ABL tyrosine kinaseremains relatively quiescent in healthy adult brain, it can be activatedin the brain of patients with CNS diseases, including neurodegenerativediseases such as, Alzheimer's disease (AD), Parkinson's disease (AD),frontotemporal dementia (FTD). Picks disease, Niemann-Pick type Cdisease (NPC) and other degenerative, inflammatory and autoimmunediseases and ageing.

An effective amount of a compound disclosed herein will generally beadministered in a single or multiple doses at an average daily dose offrom 0.01 mg to 50 mg of compound per kilogram of patient body weight,preferably from 0.1 mg to 25 mg of compound per kilogram of patient bodyweight. In general, the compounds disclosed herein may be administeredto a patient in need of such treatment in a daily dosage range of fromabout 1 mg to about 3500 mg per patient, preferably from 10 mg to 100)mg. For example, the daily dose per patient can be 10, 20, 30, 40, 50,60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 500, 600, 700, 800,900 or 1000 mg. It can be administered one or more times daily, weekly(or several days apart) or on an intermittent schedule. For example, thecompound can be administered one or more times per day on a weekly basis(e.g., every Monday), continually or for several weeks, such as 4-10weeks. Alternatively, the administration may be continued for severaldays (e.g., 2-10 days), followed by a few days (e.g., 1-30 days) withoutadministration of the compound, and the cycle may be repeatedindefinitely or repeated for a given number of times, such as 4-10.Cycles. For example, the compounds disclosed herein may be administereddaily for 5 days, then intermittently for 9 days, then administereddaily for 5 days, then intermittent for 9 days, and so on, and the cycleis repeated indefinitely or repeated 4-10 times.

EXAMPLES

The following examples are provided to provide those skilled in the artwith a complete disclosure and description of how to carry out, prepareand evaluate the methods and compounds claimed herein, which are onlyfor illustrative purpose and not constitute any limitation of the scopeof the invention.

Synthetic Method

The compounds of the present disclosure can be prepared according toconventional methods in the art and using suitable reagents, startingmaterials, and purification methods known to those skilled in the art.

The preparation of the compounds of formula (I) of the presentdisclosure is more specifically described below, but these specificmethods do not constitute any limitation to the present disclosure. Thecompounds of the present disclosure may also be conveniently prepared bycombining various synthetic methods described in the specification orknown in the art, and such combinations are readily available to thoseskilled in the art to which the present disclosure pertains.

Usually, in the preparation, each reaction is usually carried out in aninert solvent at room temperature to reflux temperature (e.g., 0° C. to100° C., preferably 0° C. to 80° C.). The reaction time is usually from0.1 to 60 hours, preferably from 0.5 to 24 hours.

Example 1 Preparation of(R)-6-(3-hydroxypyrrolidin-1-yl)-5-(isothiazol-3-yl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Compound 6)

Step 1: Synthesis of6-chloro-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide(Compound 2)

To a reaction flask were added 6-chloro-5-bromonicotinic acid (1.17 g,4.97 mmol), 4-(chlorodifluoromethoxy)aniline (0.8 g, 4.15 mmol),dissolved with 20 mL anhydrous DMF,2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU, 2.1 g, 5.39 mmol) andN,N-diisopropylethylamine (DIPEA, 534 mg, 4.15 mmol) were added, and thereaction was stirred under nitrogen protection at room temperature for18 hours. The reaction was diluted with large amount of water, extractedwith ethyl acetate for 3-4 times, the organic layers were combined,washed with brine, concentrated, purified by column chromatography,dried in vacuum to afford 1.18 g of a product, yield: 69.5%.

Step 2: Synthesis of(R)-6-(3-hydroxypyrrolidin-1-yl)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide(Compound 4)

To a reaction flask were added compound 2 (0.92 g, 2.0 mmol) and(R)-3-hydroxypyrrolidine (209.1 mg, 2.4 mmol), 2 ml isopropyl alcoholwas added, DIPEA (568.7 mg, 4.4 mmol) was added, and the reaction washeated to 140° C. and stirred for 2 hours. The temperature was cooled toroom temperature, concentrated to remove solvent, purified by silica gelcolumn chromatography to afford 813 mg of a product, yield: 88.2%.

Step 3: Synthesis of(R)-6-(3-hydroxypyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide(Compound 5)

In a reaction flask were added compound 4 (322.7 mg, 0.7 mmol),bis(pinacolato)diboron (711.03 mg, 2.8 mmol), palladium acetate (4.71mg, 0.021 mmol). Xphos (25.0 mg, 0.053 mmol) and potassium phosphate(445.8 mg, 2.1 mmol), dissolved in 10 mL anhydrous dioxane, and thereaction was heated to 60° C. in microwave and reacted for 4 hours. TLCdetected the starting material was not completely consumed,bis(pinacolato)diboron (356 mg, 1.4 mmol) was additionally added andreacted at 60° C. overnight. TLC detected the reaction was complete, thereaction was concentrated, purified by silica gel column chromatographyto afford 262 mg of a product, yield: 73.5%.

Step 4: Synthesis of(R)-6-(3-hydroxypyrrolidin-1-yl)-5-(isothiazol-3-yl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide(Compound 6)

To a reaction flask were added compound 5 (200 mg, 0.392 mmol),3-bromoisothiazole (96 mg, 0.588 mmol), Pd(dppf)Cl (32 mg, 0.02 mmol)and sodium carbonate (126 mg, 1.18 mmol), 2 mL glycol dimethyl ether and0.4 mL water were added, bubbled with nitrogen gas for 10 minutes,heated to 120° C. in microwave and reacted for 0.5 hour. After TLCdetected the reaction was complete, the reaction was concentrated,purified by silica gel column chromatography to afford 84 mg of aproduct, yield: 46%. LC-MS(APCI): m/z=467.3 (M+1)⁺; ¹H NMR (400 MHz,DMSO) δ 10.17 (s, 1H), 9.04 (s, 1H), 8.90 (s, 1H), 8.76 (d, J=2.3 Hz,1H), 8.05 (d, J=2.3 Hz, 1H), 7.86 (d, J=9.1 Hz, 2H), 7.33 (d, J=8.8 Hz,2H), 4.86 (d, J=3.4 Hz, 1H), 4.21 (s, 1H), 3.41 (dd, J=17.0, 9.3 Hz,1H), 3.29-3.18 (m, 2H), 2.90 (d, J=11.1 Hz, 1H), 1.89-1.80 (m, 1H), 1.75(s, 1H).

Example 2 Preparation of(R)-6-(3-hydroxypyrrolidin-1-yl)-5-(isothiazol-4-yl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Compound 7)

To a reaction flask were added compound 5 (200 mg, 0.392 mmol),4-bromoisothiazole (96 mg, 0.588 mmol), Pd(dppf)Cl₂ (32 mg, 0.02 mmol)and sodium carbonate (126 mg, 1.18 mmol), 2 mL glycol dimethyl ether and0.4 mL water were added, bubbled with nitrogen gas for 10 minutes, andthe reaction was heated to 120° C. in microwace for half an hour. AfterTLC detected the reaction was complete, the reaction was concentrated,purified by silica gel column chromatography to afford 58 mg of aproduct, yield: 31.7%. LC-MS(APCI): m/z=467.3 (M+1)⁺: ¹H NMR (400 MHz,DMSO) δ 10.17 (s, 1H), 9.04 (s, 1H), 8.76 (d, J=2.3 Hz, 1H), 8.70 (s,1H), 8.05 (d, J=2.3 Hz, 1H), 7.86 (d, J=9.1 Hz, 2H), 7.33 (d, J=8.8 Hz,2H), 4.86 (d, J=3.4 Hz, 1H), 4.21 (s, 1H), 3.41 (dd, J=17.0, 9.3 Hz,1H), 3.29-3.18 (m, 2H), 2.90 (d, J=11.1 Hz, 1H), 1.89-1.80 (m 1H), 1.75(s, 1H).

Example 3 Preparation of(R)-6-(3-hydroxypyrrolidin-1-yl)-5-(isothiazol-5-yl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Compound 8)

To a reaction flask were added compound 5 (200 mg, 0.392 mmol),5-bromoisothiazole (96 mg, 0.588 mmol), Pd(dppf)Cl₂ (32 mg, 0.02 mmol)and sodium carbonate (126 mg, 1.18 mmol), 2 mL glycol dimethyl ether and0.4 mL water were added, bubbled with nitrogen gas for 10 minutes, andthe reaction was heated to 120° C. in microwace for half an hour. AfterTLC detected the reaction was complete, the reaction was concentrated,purified by silica gel column chromatography to afford 97 mg of aproduct, yield: 53.1%. LC-MS(APCI): m/z=467.3 (M+1)⁺; ¹H NMR (400 MHz,DMSO) δ 10.17 (s, 1H), 9.04 (s, 1H), 8.90 (s, 1H), 8.76 (d, J=2.3 Hz,1H), 8.35 (d, J=2.3 Hz, 1H), 7.86 (d, J=9.1 Hz, 2H), 7.33 (d, J=8.8 Hz,2H), 4.86 (d, J=3.4 Hz, 1H), 4.21 (s, 1H), 3.41 (dd. J=17.0, 9.3 Hz,1H), 3.29-3.18 (m, 2H), 2.90 (d, J=11.1 Hz, 1H), 1.89-1.80 (m, 1H), 1.75(s, 1H).

Example 4 Preparation of(R)-6-(3-hydroxypyrrolidin-1-yl)-5-(1H-1,2,3-triazol-5-yl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide(Compound 12)

Step 1: Synthesis of6-chloro-5-(2-trimethylsilylethyn-1-yl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide(Compound 9)

To a reaction flask were added compound 2 (400 mg, 0.97 mmol),trimethylsilylethyne (143.4 mg, 1.46 mmol), Pd(PPh₃)₂Cl₂ (34 mg, 0.048mmol), Copper iodide (18.4 mg, 0.096 mmol) and DIPEA (377 mg, 2.92mmol), 10 mL anhydrous tetrahydrofuran was added to dissolve thesubstances, and the reaction was heated under nitrogen protection inmicrowave to 120° C. for 1 hour. After TLC detected the reaction wascomplete, the reaction was concentrated, purified by silica gel columnchromatography to afford 250 mg of a product, yield: 60.2%.

Step 2: Synthesis of6-chloro-5-ethynyl-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide(Compound 10)

To a reaction flask were added compound 9 (250 mg, 0.58 mmol), 10 mLanhydrous tetrahydrofuran was added to dissolve the substances, IMtetrabutylammonium fluoride in tetrahydrofuran (1.17 mL, 1.17 mmol) wasadded, and the reaction was reacted under nitrogen protection at roomtemperature for 20 minutes. After TLC detected the reaction wascomplete, the reaction was concentrated, purified by silica gel columnchromatography to afford 194.5 mg of a product, yield: 94.2%.

Step 3: Synthesis of6-chloro-5-(1H-1,2,3-triazol-5-yl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide(Compound 11)

To a reaction flask were added compound 10 (127 mg, 0.357 mmol) andazidotrimethylsilane (82.2 mg, 0.713 mmol), 2 mL anhydrous toluene wasadded to dissolve the substances, and the reaction was heated undernitrogen protection to 120° C. for 48 hours. The reaction wasconcentrated, purified by silica gel column chromatography to afford 45mg of a product, yield: 31.6%.

Step 4: Synthesis of(R)-6-(3-hydroxypyrrolidin-1-yl)-5-(1H-1,2,3-triazol-5-yl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Compound 12)

To a reaction flask were added compound 11 (30 mg, 0.075 mmol) and(R)-3-hydroxypyrrolidine (7.86 mg, 0.09 mmol), 2 mL isopropyl alcoholwas added, followed by DIPEA (21.32 mg, 0.165 mmol), and the reactionwas heated to 140° C. and stirred for 2 hours. The reaction was cooledto room temperature, concentrated to remove solvent, purified by silicagel column chromatography to afford 27.3 mg of a product, yield: 81%.LC-MS(APCI): m/z=451.5 (M+1)⁺; ¹H NMR (400 MHz, DMSO) δ 10.22 (s, 1H),8.75 (d, J=2.4 Hz, 1H), 8.25 (s, 1H), 8.07 (d, J=2.3 Hz, 1H), 7.89 (d,J=9.1 Hz, 2H), 7.31 (d, J=8.9 Hz, 2H), 4.81 (s, 1H), 4.14 (s, 1H),3.50-3.42 (m, 1H), 3.23-3.14 (m 0.2H), 2.80 (d, J=11.8 Hz, 1H), 1.79(dd, J=8.9, 4.4 Hz, 1H), 1.73-1.63 (m, 1H).

Example 5 Preparation of(R)-6-(3-hydroxypyrrolidin-1-yl)-5-(1H-1,2,34-tetrazol-5-yl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide(Compound 16)

Step 1: Synthesis of(R)-6-(3-tert-butyldimethylsilyloxypyrrolidin-1-yl)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide(Compound 13)

To a reaction flask were added compound 4 (200 mg, 0.434 mmol),tert-butyldimethylsilyl chloride (100 mg, 0.65 mmol) and imidazole (100mg, 1.47 mmol), 5 mL anhydrous DMF was added, and the reaction wasstirred at room temperature for 1 hour. After TLC detected the reactionwas complete, water was added to dilute the reaction, which wasextracted with ethyl acetate for 3-4 times, the organic layers werecombined, washed with brine, concentrated and purified by silica gelcolumn chromatography to afford 248 mg of a product, yield: 99%.

Step 2: Synthesis of(R)-6-(3-tert-butyldimethylsilyloxypyrrolidin-1-yl)-5-cyano-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide(Compound 14)

To a reaction flask were added compound 13 (317 mg, 0.551 mmol), zinccyanide (65 mg, 0.551 mmol) and tetrakis(triphenylphosphine)palladium(19 mg, 0.0165 mmol), 5 mL anhydrous DMF was added, and the reaction washeated to 150° C. in microwave and reacted for 10 minutes. After TLCdetected the reaction was complete, water was added to dissolve thesubstances, which was extracted with ethyl acetate for 3-4 times, theorganic layers were combined, washed with brine, concentrated andpurified by silica gel column chromatography to afford 209 mg of aproduct, yield: 93%.

Step 3: Synthesis of(R)-6-(3-tert-butyldimethylsilyloxypyrrolidin-1-yl)-5-(1H-1,2,3,4-tetrazol-5-yl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide(Compound 15)

To a reaction flask were added compound 14 (209 mg, 0.4 mmol), sodiumazide (312 mg, 4.8 mmol) and ammonium chloride (254 mg, 4.8 mmol), 5 mLanhydrous DMF was added, and the reaction was heated to 150° C. andreacted overnight. Water was added to dilute the reaction, which wasextracted with ethyl acetate for 3-4 times, the organic layers werecombined, washed with brine, concentrated and purified by silica gelcolumn chromatography to afford 102 mg of a product, yield: 45.1%.

Step 4: Synthesis of(R)-6-(3-hydroxypyrrolidin-1-yl)-5-(1H-1,2,3,4-tetrazol-5-yl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide(Compound 16)

To a reaction flask were added compound 15 (102 mg, 0.18 mmol), 3 mLmethanol was added to dissolve it, 4N HCl in methanol (0.225 ml, 0.9mmol) was added, and the reaction was stirred at room temperature for0.5 hour. The reaction was concentrated and purified by silica gelcolumn chromatography to afford 67.4 mg of a product, yield: 83%.LC-MS(APCI): m/z=452.4 (M+1)⁺; ¹H NMR (400 MHz, DMSO) δ 10.22 (s, 1H),8.75 (d, J=2.4 Hz, 1H), 8.07 (d, J=2.3 Hz, 1H), 7.89 (d, J=9.1 Hz, 2H),7.31 (d, J=8.9 Hz, 2H), 4.81 (s, 1H), 4.14 (s, 1H), 3.50-3.42 (m, 1H),3.23-3.14 (m, 2H), 2.80 (d, J=11.8 Hz, 1H), 1.79 (dd, J=8.9, 4.4 Hz,1H), 1.73-1.63 (m, 1H).

Example 6 Preparation of(R)-6-(3-hydroxypyrrolidin-1-yl)-5-(1,2,4-thiodiazol-5-yl)-N-(4-(chlorodifluoromethoxy)phenylnicotinamide(Compound 20)

Step 1: Synthesis of(R)-6-(3-hydroxypyrrolidin-1-yl)-5-cyano-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide(Compound 17)

To a reaction flask were added compound 4 (92.2 mg, 0.2 mmol), zinccyanide (23.5 mg, 0.2 mmol) and tetrakis(triphenylphosphine)palladium (7mg, 0.006 mmol), 2 mL anhydrous DMF was added, and the reaction washeated to 150° C. in microwave and reacted for 10 minutes. After TLCdetected the reaction was complete, water was added to dilute thereaction, which was extracted with ethyl acetate for 3-4 times, theorganic layers were combined, washed with brine, concentrated andpurified by silica gel column chromatography to afford 77.5 mg of aproduct, yield: 95%.

Step 2: Synthesis of(R)-6-(3-hydroxypyrrolidin-1-yl)-5-aminothioformyl-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide(Compound 18)

To a reaction flask were added compound 17 (250 mg, 0.612 mmol) andphosphorus pentasulfide (117 mg, 1.838 mmol), 10 mL ethanol was added,and the reaction was heated to 90° C. and reacted for 18 hours. Thereaction was concentrated to remove solvent, purified by silica gelcolumn chromatography to afford 75 mg of a product, yield: 27.7%.

Step 3: Synthesis of(R)-6-(3-hydroxypyrrolidin-1-yl)-5-((dimethylamino)methyleneaminothioformyl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide(Compound 19)

To a reaction flask were added compound 18 (75 mg, 0.178 mmol) andN,N-dimethylformamide dimethyl acetal (64 mg, 0.534 mmol), 5 mLanhydrous DMF was added, and the reaction was stirred at roomtemperature for 10 minutes. After TLC detected the reaction wascomplete, water was added to dilute the reaction, extracted with ethylacetate for 3-4 times, the organic layers were combined, washed withbrine, concentrated and purified by silica gel column chromatography toafford 40 mg of a product, yield: 45.2%.

Step 4: Synthesis of(R)-6-(3-hydroxypyrrolidin-1-yl)-5-(1,2,4-thiodiazol-5-yl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Compound 20)

To a reaction flask were added compound 19 (40 mg, 0.08 mmol) andpyridine (12.6 mg, 0.16 mmol), 2.5 mL ethanol was added to dissolve it,hydroxylamine-O-sulfonic acid (10 mg, 0.088 mmol) in 1.5 mL methanol wasslowly added dropwise, and after addition the reaction was stirred atroom temperature for 1 hour. After TLC detected the reaction wascomplete, concentrated to remove solvent, purified by silica gel columnchromatography to afford 21 mg of a product, yield: 56.1%. LC-MS(APCI):m/z=468.6 (M+1)⁺; ¹H NMR (400 MHz, DMSO) δ 10.31 (s, 1H), 9.01 (s, 1H),8.88 (d. J=2.3 Hz, 1H), 8.33 (d, J=2.3 Hz, 1H), 7.87 (d, J=9.1 Hz, 2H),7.35 (d, J=8.9 Hz, 2H), 5.32 (t, J=4.8 Hz, 1H), 4.27 (s, 1H), 3.56 (d,J=7.4 Hz, 1H), 3.28 (dd, J=13.2, 5.3 Hz, 2H), 2.93 (d, J=12.0 Hz, 1H),1.92-1.85 (m, 1H), 1.80 (dt, J=15.9, 6.5 Hz, 1H.

Example 7 Preparation of(R)-6-(3-fluoropyrrolidin-1-yl)-5-(isothiazol-4-yl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide(Compound 23)

Step 1: Synthesis of(R)-6-(3-fluoropyrrolidin-1-yl)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide(Compound 21)

To a reaction flask were added compound 2 (0.90 g, 2.19 mmol) and(R)-3-fluoropyrrolidine hydrochloride (330 mg, 2.63 mmol), 15 mLisopropyl alcohol, and DIPEA (621 mg, 4.82 mmol) were added, and thereaction was heated to 140° C. and stirred for 2 hours. After cooling toroom temperature, the reaction was concentrated to remove solvent,purified by silica gel column chromatography to afford 841 mg of aproduct, yield, 83%.

Step 2: Synthesis of(R)-6-(3-fluoropyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide(Compound 22)

In a reaction flask were added compound 21 (628 mg, 1.35 mmol),bis(pinacolato)diboron (1.03 g, 4.06 mmol), palladium acetate (10 mg,0.041 mmol), Xphos (50 mg, 0.101 mmol) and potassium phosphate (861 mg,4.06 mmol), 20 mL anhydrous dioxane was added to dissolve thesubstances, and the reaction was heated to 60° C. in microwave andreacted for 4 hours. TLC detected the starting material was notcompletely consumed, bis(pinacolato)diboron (1.03 g, 4.06 mmol) wasadditionally added and then reacted at 60° C. overnight. After TLCdetected the reaction was complete, the reaction was concentrated,purified by silica gel column chromatography to afford 514.3 mg of aproduct, yield: 75%.

Step 3: Synthesis of(R)-6-(3-fluoropyrrolidin-1-yl)-5-(isothiazol-4-yl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide(Compound 23)

To a reaction flask were added compound 22 (100 mg, 0.195 mmol),4-bromoisothiazole (50 mg, 0.293 mmol), Pd(dppf)Cl₂ (5 mg, 0.006 mmol)and sodium carbonate (60 mg, 0.558 mmol), 5 mL glycol dimethyl ether and0.9 mL water were added, bubbled with nitrogen gas for 10 minutes, andthe reaction was heated to 100° C. in microwave and reacted for half anhour. After TLC detected the reaction was complete, the reaction wasconcentrated, purified by silica gel column chromatography to afford 42mg of a product, yield: 46%. LC-MS(APCI): m/z=469.5 (M+1)⁺. ¹H NMR (400MHz, CDCl₃) δ 8.69 (d, J=2.4 Hz, 1H), 8.58 (d, J=9.6 Hz, 2H), 7.94 (d,J=2.4 Hz, 1H), 7.74 (s, 1H), 7.67 (d, J=9.0 Hz, 2H), 7.23 (s, 1H), 5.21(d, J=52.0 Hz, 1H), 3.56 (d, J=3.1 Hz, 1H), 3.52-3.44 (m, 2H), 3.30 (t,J=9.7 Hz, 1H), 2.26-2.19 (m, 1H), 2.03-1.97 (m, 1H).

Example 8 Preparation of(R)-6-(3-fluoropyrrolidin-1-yl)-5-(isothiazol-5-yl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Compound 24)

To a reaction flask were added compound 22 (100 mg, 0.195 mmol),5-bromoisothiazole (50 mg, 0.293 mmol), Pd(dppf)Cl₂ (5 mg, 0.006 mmol)and sodium carbonate (60 mg, 0.558 mmol), 5 mL glycol dimethyl ether and0.9 mL water were added, bubbled with nitrogen gas for 10 minutes, andthe reaction was heated to 100° C. in microwave and reacted for half anhours. After TLC detected the reaction was complete, the reaction wasconcentrated, purified by silica gel column chromatography to afford 45mg of a product, yield: 48%. LC-MS(APCI): m/z=469.5 (M+1)⁺. ¹H NMR (400MHz, CDCl₃) δ 8.73 (d, J=2.3 Hz, 1H), 8.49 (d, J=1.4 Hz, 1H), 7.97 (d,J=2.3 Hz, 1H), 7.90 (s, 1H), 7.66 (d, J=9.0 Hz, 2H), 7.24 (s, 1H),7.23-7.20 (m, 2H), 5.30 (s, 1H), 3.66 (dd, J=13.6, 3.2 Hz, 1H),3.60-3.53 (m, 2H), 3.36 (t, J=9.8 Hz, 1H), 2.29-2.18 (m, 1H), 2.10-1.94(m 1H).

Example 9 Preparation of(R)-6-(3-fluoropyrrolidin-1-yl)-(1,2,4-thiodiazol-5-yl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide(Compound 28)

According to the same procedures as those used in the precedingExamples, the title product compound 28 was obtained. LC-MS(APCI):m/z=470.8 (M+1)⁺. ¹H NMR (400 MHz, DMSO) δ 10.31 (s, 1H), 9.01 (s, 1H),8.88 (d. J=2.3 Hz, 1H), 8.33 (d, J=2.3 Hz, 1H), 7.87 (d, J=9.1 Hz, 2H),7.35 (d, J=8.9 Hz 2H), 5.32 (t, J=4.8 Hz, 1H), 4.27 (s, 1H), 3.56 (d,J=7.4 Hz, 1H), 3.28 (dd, J=13.2, 5.3 Hz, 2H), 2.93 (d, J=12.0 Hz, 1H),1.92-1.85 (m, 1H), 1.80 (dt, J=15.9, 6.5 Hz, 1H).

Example 10 Preparation of(R)-6-(3-dimethylaminopyrrolidin-1-yl)-5-(isothiazol-4-yl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide(Compound 31)

Step 1: Synthesis of(R)-6-(3-dimethylaminopyrrolidin-1-yl)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide(Compound 29)

To a reaction flask were added compound 2 (0.90 g, 2.19 mmol) and(R)-3-dimethylaminopyrrolidine hydrochloride (300 mg, 2.63 mmol), 15 mLisopropyl alcohol, and DIPEA (621 mg, 4.82 mmol) were added, and thereaction was heated to 140° C. and stirred for 2 hours. After cooling toroom temperature, the reaction was concentrated to remove solvent,purified by silica gel column chromatography to afford 1.06 g of aproduct, yield: 99%.

Step 2: Synthesis of(R)-6-(3-dimethylaminopyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide(Compound 30)

In a reaction flask were added compound 29 (633 mg, 1.3 mmol),bis(pinacolato)diboron (0.98 g, 3.89 mmol), palladium acetate (25 mg,0.039 mmol), Xphos (50 mg, 0.1 mmol) and potassium phosphate (826 mg,3.9 mmol), 20 mL anhydrous dioxane was added to dissolve the substances,and the reaction was heated to 60° C. in microwave and reacted for 4hours. TLC detected the starting material was not completely consumed,bis(pinacolato)diboron (0.98 g, 3.89 mmol) was additionally added andreacted at 60° C. overnight. After TLC detected the reaction wascomplete, the reaction was concentrated, purified by silica gel columnchromatography to afford 564 mg of a product, yield 81%.

Step 3: Synthesis of(R)-6-(3-dimethylaminopyrrolidin-1-yl)-5-(isothiazol-4-yl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Compound 31)

To a reaction flask were added compound 30 (100 mg, 0.186 mmol),4-bromoisothiazole (50 mg, 0.279 mmol), Pd(dppf)Cl₂ (5 mg, 0.006 mmol)and sodium carbonate (60 mg, 0.558 mmol), 5 mL glycol dimethyl ether and0.9 mL water were added, bubbled with nitrogen gas for 10 minutes, andthe reaction was heated to 100° C. in microwave and reacted for half anhour. After TLC detected the reaction was complete, the reaction wasconcentrated, purified by silica gel column chromatography to afford 78mg of a product, yield: 85%. LC-MS(APCI): m/z=494.7 (M+1)⁺. ¹H NMR (400MHz, CDCl₃) δ 8.67 (s, 1H), 8.54 (d, J=4.3 Hz, 2H), 7.96 (s, 1H), 7.91(s, 1H), 7.67 (d, J=8.8 Hz, 2H), 7.22 (d, J=8.6 Hz, 2H), 3.43-3.34 (m,1H), 3.34-3.21 (m, 2H), 3.18 (dd, J=17.9, 9.0 Hz, 1H), 2.67 (s, 1H),2.23 (s, 6H), 2.05 (d, J=6.5 Hz, 1H), 1.76 (dd, J=20.3, 10.0 Hz, 1H).

Example 11 Preparation of(R)-6-(3-dimethylaminopyrrolidin-1-yl-5-(isothiazol-5-yl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide(Compound 32)

To a reaction flask were added compound 30 (100 mg, 0.186 mmol),5-bromoisothiazole (50 mg, 0.279 mmol), Pd(dppf)Cl₂ (5 mg, 0.006 mmol)and sodium carbonate (60 mg, 0.558 mmol), 5 mL glycol dimethyl ether and0.9 mL water were added, bubbled with nitrogen gas for 10 minutes, andthe reaction was heated to 100° C. in microwave and reacted for half anhour. After TLC detected the reaction was complete, the reaction wasconcentrated, purified by silica gel column chromatography to afford 54mg of a product, yield: 58.8%. LC-MS(APCI): m/z=494.7 (M+1)⁺. ¹H NMR(400 MHz, CDCl₃) δ 8.72 (d, J=2.3 Hz, 1H), 8.46 (d, J=1.5 Hz, 1H), 8.40(s, 1H), 8.01 (d, J=2.3 Hz, 1H), 7.72 (d, J=9.0 Hz, 2H), 7.24-7.17 (m,3H), 3.50 (dd, J=10.8, 7.1 Hz, 1H), 3.42 (t. J=9.6 Hz, 1H), 3.32 (dd,J=9.3, 4.4 Hz, 2H), 2.91-2.84 (m, 1H), 2.35 (s, 6H), 2.10 (dd, J=11.6,6.0 Hz, 1H), 1.91 (dd, J=20.5, 10.4 Hz, 1H).

Example 12 Preparation of(R)-6-(3-dimethylaminopyrrolidin-1-yl)-5-(1,2,4-thiodiazol-5-yl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide(Compound 36)

According to the same procedures as those used in the preceding Examplesthe title product compound 36 was finally obtained. LC-MS(APCI):m/z=495.0 (M+1)⁺. ¹H NMR (400 MHz, DMSO) δ 10.34 (s, 1H), 9.02 (s, 1H),8.88 (d, J=2.3 Hz, 1H), 8.36 (d, J=2.3 Hz, 1H), 7.87 (d, J=9.1 Hz, 2H),7.35 (d, J=9.0 Hz, 2H), 3.50 (dd, J=10.8, 7.1 Hz, 1H), 3.42 (t, J=9.6Hz, 1H), 3.32 (dd, J=9.3, 4.4 Hz, 2H), 2.91-2.84 (m, 1H), 2.35 (s, 6H),2.10 (dd. J=11.6, 6.0 Hz, 1H), 1.91 (dd, J=20.5, 10.4 Hz, 1H).

Example 13 Preparation of6-(3-hydroxy-4-fluoropyrrolidin-1-yl)-5-(isothiazol-4-yl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide(Compound 42)

Step 1: Synthesis of 3-hydroxy-4-fluoro-N-tert-butoxycarbonylpyrrolidine(Compound 38)

To a reaction flask were added3-tert-butoxycarbonyl-6-oxa-3-azabicyclo[3.1.0]hexane (1.11 g, 6.0 mmol)and triethylamine trihydrofluoride (967.3 mg, 7.2 mmol), and thereaction was heated to 100° C. and stirred overnight. After cooling toroom temperature, the reaction was purified by silica gel columnchromatography to afford 881 mg of a product, yield: 71.6%.

Step 2: Synthesis of 3-hydroxy-4-fluoropyrrolidine (Compound 39)

To a reaction flask were added compound 38 (881 mg, 4.29 mmol) and 4 MHCl in dioxane (27 ml, 107.4 mmol), and the reaction was stirred at roomtemperature for 3-4 hours. After TLC detected the reaction was complete,the reaction was concentrated to remove solvent, which was used in thenext step without purification.

Step 3: Synthesis of6-(3-hydroxy-4-fluoropyrrolidin-1-yl)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide(Compound 40)

To a reaction flask were added compound 2 (883 mg, 2.15 mmol) andcompound 39 (276.1 mg, 2.63 mmol), 15 mL isopropyl alcohol was added,DIPEA (610 mg, 4.73 mmol) was added, and the reaction was heated to 140°C. and stirred for 2 hours. After cooling to room temperature, thereaction was concentrated to remove solvent, purified by silica gelcolumn chromatography to afford 896 mg of a product, yield: 87%.

Step 4: Synthesis of6-(3-hydroxy-4-fluoropyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide(Compound 41)

In a reaction flask were added compound 40 (650 mg, 1.35 mmol),bis(pinacolato)diboron (1.03 g, 4.06 mmol), palladium acetate (10 mg,0.045 mmol), Xphos (50 mg, 0.1 mmol) and potassium phosphate (861 mg,4.06 mmol), 20 mL anhydrous dioxane was added to dissolved thesubstances, and the reaction was heated to 60° C. in microwave andreacted for 4 hours. TLC detected the starting material was notcompletely consumed, bis(pinacolato)diboron (1.03 g, 4.06 mmol) wasadditionally added and reacted at 60° C. overnight. After TLC detectedthe reaction was complete, it was concentrated, purified by silica gelcolumn chromatography to afford 664 mg of a product, yield: 93.4%.

Step 5: Synthesis of6-(3-hydroxy-4-fluoropyrrolidin-1-yl)-5-(isothiazol-4-yl)-N-(4-(chlorodifluoromethoxy)phenyl5)nicotinamide (Compound 42)

To a reaction flask were added compound 41 (100 mg, 0.19 mmol),4-bromoisothiazole (50 mg, 0.27 mmol), Pd(dppf)Cl₂ (5 mg, 0.006 mmol)and sodium carbonate (60 mg, 0.558 mmol), 5 mL glycol dimethyl ether and0.9 mL water were added, bubbled with nitrogen gas for 10 minutes, andthe reaction was heated to 100° C. in microwave and reacted for half anhours. After TLC detected the reaction was complete, the reaction wasconcentrated, purified by silica gel column chromatography to afford 58mg of a product, yield: 63%. LC-MS(APCI): m/z=485.3 (M+1)⁺. ¹H NMR (400MHz, CDCl₃) δ 10.23 (s, 1H), 9.09 (s, 1H), 8.77 (d, J=2.0 Hz, 1H), 8.72(s, 1H), 8.10 (d, J=2.0 Hz, 1H), 7.87 (d, J=9.0 Hz, 2H), 7.34 (d, J=8.7Hz, 2H), 5.47 (d, J=3.5 Hz, 1H), 4.94 (d, J=51.5 Hz, 1H), 4.18 (s, 1H),3.64 (ddd, J=41.8, 13.5, 3.1 Hz, 1H), 3.43-3.38 (m, 1H), 3.02 (d, J=11.9Hz, 1H).

Example 14 Preparation of6-(3-hydroxy-4-fluoropyrrolidin-1-yl)-5-(isothiazol-5-yl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide(Compound 43)

To a reaction flask were added compound 41 (100 mg, 0.19 mmol),5-bromoisothiazole (50 mg, 0.27 mmol), Pd(dppf)Cl₂ (5 mg, 0.006 mmol)and sodium carbonate (60 mg, 0.558 mmol), 5 mL glycol dimethyl ether and0.9 mL water were added, bubbled with nitrogen gas for 10 minutes, andthe reaction was heated to 100° C. in microwave and reacted for half anhours. After TLC detected the reaction was complete, the reaction wasconcentrated, purified by silica gel column chromatography to afford 29mg of a product, yield: 31.5%. LC-MS(APCI): m/z=485.3 (M+1)⁺. ¹H NMR(400 MHz, DMSO) δ 10.29 (s, 1H), 8.82 (d, J=2.3 Hz, 1H), 8.65 (d, J=1.61Hz, 1H), 8.15 (d. J=2.3 Hz, 1H), 7.87 (d, J=9.1 Hz, 2H), 7.50 (d, J=1.6Hz, 1H), 7.34 (d, J=9.0 Hz, 2H), 5.50 (d, J=2.8 Hz, 1H), 4.97 (d, J=52.1Hz, 1H), 4.21 (s, 1H), 3.75 (ddd, J=41.8, 13.6, 3.3 Hz, 1H), 3.51 (d,J=12.1 Hz, 1H), 3.46-3.36 (m, 1H), 3.08 (d, J=11.9 Hz, 1H).

Example 15 Preparation of6-(3-hydroxy-4-fluoropyrrolidin-1-yl)-5-(1,2,4-thiodiazol-5-yl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide(Compound 47)

According to the same procedures as those used in the precedingExamples, the title product compound 47 was finally obtained.LC-MS(APCI): m/z=486.8 (M+1)⁺. ¹H NMR (400 MHz, DMSO) δ 10.35 (s, 1H),9.04 (s, 1H), 8.90 (d, J=2.3 Hz, 1H), 8.37 (d, J=2.3 Hz, 1H), 7.86 (t,J=6.0 Hz, 2H), 7.35 (d, J=8.9 Hz, 2H), 5.54 (d, J=3.3 Hz, 1H), 5.00 (d,J=52.8 Hz, 1H), 4.25 (s, 1H), 3.91-3.77 (m, 1H), 3.61 (d, J=12.1 Hz,1H), 3.46-3.38 (m, 1H), 3.02 (d, J=12.2 Hz, 1H).

Biological Activity Test Example 16: Cytotoxicity Experiment

The inhibitory effect of the Example compounds on the activity of Ba/F₃parent cell, Ba/F₃ Bcr-Abl^(T315I) cell was examined.

Materials and reagents: RPMI-1640 medium (GIBCO, Cat. No. A10491-01),fetal bovine serum (GIBCO, Cat. No. 10099141), antibiotics(penicillin-streptomycin), IL-3 (PeproTech), puromycin; Cell lines:Ba/F₃ parental cell, Ba/F₃ Bcr-Abl^(T315I) (purchased from AmericanStandard Biological Collection Center, ATCC), live cell assay kitCellTiter-Glo4 (Promega, Cat. No. G7572), 96-well cell culture platewith black wall and transparent flat bottom (Corning, Cat. No. 3340).

Experimental Procedures:

1. Preparation of cell plate: Ba/F₃ parental cells, Ba/F₃Bcr-Abl^(T315I) cells were seeded in 96-well plates, and 8 ng/ml IL-3was added to Ba/F₃ parental cells. The cell plates were placed in carbondioxide culture and incubated overnight.

2. Preparation of test compounds: The test compounds were dissolved inDMSO and subjected to a 3.16-fold gradient dilution in triplicate, 9concentrations were obtained, starting from the concentration of 10 μM.

3. Treatment of Cells with compounds: Compounds at variousconcentrations were transferred to cell plates. The cell plates wereincubated in a carbon dioxide incubator for 3 days.

4. Detection: CellTiter-Glo4 reagent was added to the cell plates, whichwere incubated for 30 minutes at room temperature to stabilize theluminescence signal. Readings were performed using a PerkinElmerEnvision multi-label analyzer.

The results of in vitro inhibition of cell proliferation in the examplesare summarized in Table 1 below, wherein A represents IC₅₀≤100 nM, Brepresents 100 nM<IC₅₀≤500 nM, C represents 500 nM<IC₅₀≤1000 nM, and Drepresents IC₅₀>1000 nM.

TABLE 1 cytotoxic effects of the Example compounds Ba/F₃ parent cellsBa/F₃ Bcr-Abl1^(T315I) Example No. IC₅₀ IC₅₀ Example 1 D B Example 2 D AExample 3 D A Example 4 D C Example 5 D D Example 6 D B

The experimental results show that, the compounds disclosed hereinexhibit relatively low inhibitory activity against Ba/F₃ cells that arerelated to drug side effects (IC₅₀ greater than 1000 nM), and exhibitexcellent inhibitory activity against Ba/F₃ Bcr-Abl T^(T315I) mutantcells (the optimal IC₅≤100 nM). Therefore, the compounds disclosedherein can be used as Bcr-Abl inhibitors for use in the treatment ofpatients with tumor that is resistant to existing tyrosine kinaseinhibitor (TKI) treatment, with have good prospects, such as chronic,blast, and accelerated phases of chronic myeloid leukemia (CML) patientsand chronic myeloid leukemia and acute lymphoblastic leukemia patientswith Philadelphia chromosome-positive (Ph⁺).

Furthermore, the compounds disclosed herein also have an excellenttherapeutic index (obtained by dividing the IC₅₀ of the Ba/F₃ parentcells by the IC₅₀ of Ba/F Bcr-Abl^(T315I)), for example, the compound ofExample 2 has a therapeutic index greater than 180, and the compound ofExample 3 has a therapeutic index greater than 90.

Example 17: Pharmacokinetic Experiment in Rats

6 Male Sprague-Dawley rats, 7-8 weeks old, weighted 210 g, divided into2 groups with 3 rats in each group, were intravenously (2 mg/kg) ororally (20 mg/kg) given a single dose of compound, and differences inpharmacokinetics of the rats were compared.

Rats were fed with a standard diet and water. Fasting began 16 hoursbefore the test. The drugs were dissolved in PEG400 and dimethylsulfoxide. Blood was collected from the eyelids at a time point of 0.083hour, 0.25 hour, 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours,12 hours, and 24 hours after administration.

Rats were briefly anesthetized after inhalation of ether, and 300 μL ofblood samples were collected from the eyelids to test tubes. There was30 μL of 1% heparin salt solution in the test tube. The tubes were driedovernight at 60° C. before use. After the blood sample was collected atthe last time point, rats were anesthetized with ether and sacrificed.

Immediately after the collection, blood samples were sufficiently mixedby gently inverting the tube at least 5 times, and were placed on ice.Blood samples were centrifuged at 5000 rpm for 5 minutes at 4° C. toseparate plasma from red blood cells, 100 μL of the plasma was pipettedinto a clean plastic centrifuge tube, marking the name of the compoundand collecting time. Plasma was stored at −80° C. prior to analysis. Theconcentration of the compounds disclosed herein in plasma was determinedby LC-MS/MS. Pharmacokinetic parameters were calculated based on drugconcentrations in plasma of each animal at different time points.

In this experiment, ABL-001 was used as a positive control, and theexperimental results are shown in Table 2 below.

TABLE 2 PK parameters of Example compounds in rats ABL-001 Example 2 PKparameters IV PO IV PO C_(max) (ng/mL) 10081.3  1766.2 5282.5  2582.0AUC_(last) (h*ng/mL)  6900.6  13706.4  5450.5  21093.8  MRT_(INF pred)(h)     1.12     5.52    1.17     5.13 Vz _(pred) (L/kg)     0.54    5.14    0.57     2.56 Cl _(pred) (L/kg)     0.30     1.66    0.37    0.96 F (%) 19.86 38.70

The experimental results indicate that the compounds disclosed hereinhave better pharmacokinetic properties. For example, after orallyadministering the compound of Example 2 and ABL-001 to rats, thecompound of Example 2 was found to have better metabolicparameters−maximum plasma exposure (C_(max)), plasma exposure(AUC_(last)), and oral availability (F %).

Example 18: Pharmacodynamic Evaluation of BA/F3 (BCR-ABL^(T315)I) inSubcutaneous Tumor Model

Experimental animals: 32 NOD/SCID mice, female, 7-8 weeks old (age attumor cell inoculation), average body weight 21.8 g, were purchased fromBeijing Huafukang Bioscience Co., Inc, animal certificate number:11401300068166. Feeding environment: SPF level.

Environmental conditions of the breeding room for experimental animals:The experimental animals were kept in separate ventilated boxes withconstant temperature and humidity, wherein the temperature of thebreeding room was 22.3-24.5° C., the humidity was 51-58%, theventilation is 10-20 times/hour, and 12 h/12 h day and night; ratfull-price pellet feed, that was sterilized with cobalt 60 radiation,was continuous supplied and freely accessible without limitation, anddrinking tap water (used after high-pressure steam sterilization), wascontinuous supplied in water bottle and freely accessible. The rat boxesare polysulfone mouse boxes, which were used after autoclaving. Thespecification of the boxes is 325 mm×210 mm×180 mm, the bedding isautoclaved corn cob, 4 animals per box. The IACUC approval number,experiment number, experiment starting time, project leader,experimenter, animal source, group, animal number, etc. were indicatedon the cage; and experimental animals were marked with ear tags.

Methods: Each NOD/SCID mouse was subcutaneously inoculated with 5×10⁶BA/F3(BCR-ABL^(T315I)) cells in the right dorsal area, wherein the cellswere resuspended in PBS (0.1 ml/mouse), to establish a subcutaneoustumor model. The tests were divided into vehicle control group, positivecontrol ABL001 15 mg/kg group, the compound of Example 2 15 mg/kg group;6 mice in each group. The mice were dosed twice a day, vehicle controlgroup was administered for 15 days, positive control ABL001 15 mg/kg wasadministered for 19 days, and the compound of Example 2 15 mg/kg groupwas administered for 19 days. The efficacy was evaluated according tothe relative tumor growth inhibition rate (TGI), and the safetyevaluation was performed according to the body weight changes and deathsof the animals.

The experimental protocols for animal experiment disclosed herein werereviewed and approved by the CrownBio IACUC committee. During theexperiment, the procedures of the animal experiment were carried outaccording to the requirements of AAALAC. After tumor inoculation, theeffects of tumor growth and treatment on normal animal behavior wereroutinely monitored, including experimental animal activity, feeding anddrinking, weight gain or loss, eye, hair and other abnormalities.Abnormal clinical symptoms observed during the experiment were recordedin the raw data. Mice body weight and tumor size were measured andrecorded three times per week during the experiment. The mice wereweighed before each administration and administered according to theweight thereof.

Relative tumor growth inhibition rate TGI (%): TG %=(1−T/C)×100%. T/C %is the relative tumor proliferation rate, that is, the percentage oftumor volume or tumor weight of the treatment group and the controlgroup at a certain time point. T and C are the relative tumor volume(RTV) or tumor weight (TW) of the treatment group and the control groupat a specific time point, respectively.

Statistical analysis. All experimental results were expressed as meanstandard error (x±s), and the significant difference of the tumor volumeat 12 days after grouping between the control group and each treatmentgroup was evaluated with one-way ANOVA, and significant difference ofthe tumor volume between the control group and each treatment group orbetween each treatment group was evaluated using Games-Howell(heterogeneity of variance), p<0.05 was considered to be significant.

Experimental Results:

In the BA/F₃ (BCR-ABL^(T315I)) subcutaneous tumor model, the compoundsdisclosed herein have better anti-tumor effects and better safety. Forexample, the relative tumor growth inhibition rate (TGI) of the compoundof Example 2 was at least 20% higher than that of ABL-001: during theexperiment, the average body weight in the ABL-001 group decreased by5%, while in the compound of Example 2 group the average body weight ofthe mice increased, and it can be concluded from the changes in bodyweight of the mice that: the compound of Example 2 was safer thanABL-001.

It is to be understood that the examples are merely illustrative of theinvention and are not intended to limit the scope of the invention, andthe experimental methods in which the specific conditions are notindicated, are carried out generally in accordance with conventionalconditions, or in accordance with the conditions suggested by themanufacturer. Parts and percentages are parts by weight and percentageby weight unless otherwise stated.

The above is a further detailed description of the present disclosure inconnection with the specific preferred embodiments, and the specificembodiments of the present disclosure are not limited to thedescription. It will be apparent to those skilled in the art that thepresent disclosure may be practiced by making various simple deductionand replacement, without departing from the spirit and scope of theinvention.

1-13. (canceled)
 14. A compound of formula (I), or a pharmaceuticallyacceptable salt, a stereoisomer, a solvate, or a hydrate thereof:

wherein: Y₁ is selected from CR_(a) and N; Y is independently selectedfrom CR_(a) and N; R₁ is selected from hydrogen, halo, nitrile, nitro,C₁₋₆ alkyl, and C₁₋₆ haloalkyl, wherein the said C₁₋₆ alkyl or C₁₋₆haloalkyl is optionally substituted by R_(1a) group; R₂ is selected fromhydrogen, C₁₋₆ alkyl, and C₁₋₆ haloalkyl, wherein the said C₁₋₆ alkyl orC₁₋₆ haloalkyl is optionally substituted by R_(2a) group; Z is achemical bond, O, S(O)₀₋₂, or NR_(b); or —Z—R₂ together form —SF₅; Ar is

wherein X₁ is S, X₂ to X₄ are independently selected from CR and N; andone of X₂, X₃ and X₄ is a C atom that connects the parent core; Het is

wherein X₉ is selected from O, S, NR_(b), and C(R)₂; m is 0, 1, or 2; nis 0, 1, 2, 3, 4, 5, or 6; R_(a) is independently selected fromhydrogen, halo, nitrile, nitro, hydroxy, —NH₂, —NHC₁₋₆ alkyl, —N(C₁₋₆alkyl)₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl, and C₁₋₆ alkoxyl; R_(b) isindependently selected from hydrogen, C₁₋₆ alkyl, and C₁₋₆ haloalkyl;R_(1a), R_(2a), and R are independently selected from hydrogen, halo,hydroxy, —NH₂, —NHC₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkoxyl, C₃₋₇ cycloalkyl, C₃₋₇ heterocyclyl, C₆₋₁₀ aryl,and C₅₋₁₀ heteroaryl; or two R groups on the same or adjacent atoms maytogether form C₃₋₇ cycloalkyl, C₃₋₇ heterocyclyl, C₆₋₁₀ aryl, or C₅₋₁₀heteroaryl.
 15. The compound according to claim 14, which is formula(Ia), or a pharmaceutically acceptable salt, a stereoisomer, a solvateor a hydrate thereof:

wherein Ar and Het are as defined in claim
 14. 16. The compoundaccording to claim 14, or a pharmaceutically acceptable salt, astereoisomer, a solvate, or a hydrate thereof, wherein: Het is

wherein X₉ is C(R)₂, and m, n, and R are as defined in claim
 14. 17. Thecompound according to claim 14, or a pharmaceutically acceptable salt, astereoisomer, a solvate, or a hydrate thereof, wherein Het is selectedfrom the following groups that are optionally substituted by one, two,three or more R:

wherein R are as defined in claim
 14. 18. The compound according toclaim 14, or a pharmaceutically acceptable salt, a stereoisomer, asolvate, or a hydrate thereof, wherein Het is selected from thefollowing groups:


19. The compound according to claim 14, which is formula (Ib), or apharmaceutically acceptable salt, a stereoisomer, a solvate, or ahydrate thereof:

wherein: Ar is selected from the following groups that are optionallysubstituted by one or two R:

and R is selected from hydrogen, halo, hydroxy, —NH₂, —NHC₁₋₆ alkyl, and—N(C₁₋₆ alkyl)₂.
 20. The compound according to claim 14, which isformula (Ib), or a pharmaceutically acceptable salt, a stereoisomer, asolvate, or a hydrate thereof:

wherein: Ar is selected from the following groups that are optionallysubstituted by one or two R:

and R is selected from hydrogen and hydroxy.
 21. The compound accordingto claim 14, which is formula (Ib), or a pharmaceutically acceptablesalt, a stereoisomer, a solvate, or a hydrate thereof:

wherein: Ar is selected from the following groups that are optionallysubstituted by one or two R:

and R is selected from hydrogen, halo, and hydroxy.
 22. The compoundaccording to claim 14, which is formula (Ib), or a pharmaceuticallyacceptable salt, a stereoisomer, a solvate or a hydrate thereof:

wherein: Ar is selected from the following groups that are optionallysubstituted by one or two R:

and R is selected from hydrogen and hydroxy.
 23. The compound accordingto claim 14, or a pharmaceutically acceptable salt, a stereoisomer, asolvate, or a hydrate thereof, wherein the said compound is selectedfrom:


24. The compound according to claim 23, having the structure:

or a pharmaceutically acceptable salt thereof.
 25. The compoundaccording to claim 23, having the structure:

or a pharmaceutically acceptable salt thereof.
 26. The compoundaccording to claim 23, having the structure:

or a pharmaceutically acceptable salt thereof.
 27. The compoundaccording to claim 23, having the structure:

or a pharmaceutically acceptable salt thereof.
 28. A pharmaceuticalcomposition, comprising the compound according to claim 14, or apharmaceutically acceptable salt, a stereoisomer, a solvate or a hydratethereof, and pharmaceutically acceptable excipients.
 29. Apharmaceutical composition, comprising the compound according to claim24 or a pharmaceutically acceptable salt thereof, and pharmaceuticallyacceptable excipients.
 30. A pharmaceutical composition, comprising thecompound according to claim 25 or a pharmaceutically acceptable saltthereof, and pharmaceutically acceptable excipients.
 31. Apharmaceutical composition, comprising the compound according to claim26 or a pharmaceutically acceptable salt thereof, and pharmaceuticallyacceptable excipients.
 32. A pharmaceutical composition, comprising thecompound according to claim 27 or a pharmaceutically acceptable saltthereof, and pharmaceutically acceptable excipients.
 33. A method oftreating and/or preventing a Bcr-Abl mediated disease in a subject,comprising administering to the subject a compound according to claim14, or a pharmaceutically acceptable salt, a stereoisomer, a solvate, ora hydrate thereof.
 34. The method according to claim 33, wherein theBcr-Abl mediated disease is a proliferative disease selected from: solidtumor, sarcoma, acute lymphocytic leukemia, acute myeloid leukemia,chronic lymphocytic leukemia, chronic myeloid leukemia, gastrointestinalstromal tumor, thyroid cancer, gastric cancer, rectal cancer, multiplemyeloma, neoplasia, and other proliferative disease or proliferativediseases; or the Bcr-Abl mediated disease is metastatic invasive cancer,virus infection, or a CNS disease.